研究者基本情報

• 医学博士, 北海道大学医学研究院

• https://researchmap.jp/wanglei

• https://jglobal.jst.go.jp/detail?JGLOBAL_ID=201301082476201567

• 201301082476201567

• 動物モデル
• NGS解析
• シグナル伝達
• 癌幹細胞
• 脳腫瘍

• ライフサイエンス, 実験病理学, 腫瘍病理学

研究活動情報

• Induction of Meningioma Stem Signature via Hydrogel Reprogramming and Application of Meningioma Stem Cell Marker CXCR4 to Pathological Diagnosis and Treatment.
  Yoshitaka Oda; Masumi Tsuda; Lei Wang; Jun Suzuka; Sayaka Yuzawa; Koki Ise; Umma Habiba; Jintao He; Satoshi Tanikawa; Hirokazu Sugino; Zen-Ichi Tanei; Christian Mawrin; Jian Ping Gong; Shinya Tanaka
  Biotechnology and bioengineering, 2026年02月27日, ［国際誌］
  英語, 研究論文（学術雑誌）, Meningiomas account for about 40% of all primary brain tumors. How ever effective treatments for recurrent or inoperable cases remain limited. We previously demonstrated that culturing cancer cells on specific hydrogels efficiently induces cancer stem cells across multiple cancer types, a process we termed hydrogel activated reprogramming (HARP) phenomenon. In this study, we aimed to identify key molecules involved in the induction of meningioma stem cells through hydrogel-based culture. Meningioma cells cultured on hydrogels were analyzed for expression of established stem cell markers and for tumorigenicity. Microarray analysis was performed to identify meningioma stem cell specific markers and to evaluate the application of these marker molecules as a therapeutic targets or as diagnostic tools for pathological grading. Canonical stem cell markers including Nanog, and Oct3/4 were upregulated in culturing meningioma cells on hydrogels. Comprehensive gene expression analysis identified some molecules involved in cancer stem cell activity among which CXCR4 was selected as a potential therapeutic target. Stimulation of CXCR4 with its ligand CXCL12 resulted in increased expression of stem cell markers. In human meningioma pathological specimens and cultured cell lines, there was a correlation between CXCR4 expression levels and NF2 mutations and/or deletions. CXCR4 immunohistochemistry was frequently positive in cases with brain invasion along with brain invasion area. These findings suggest that CXCR4 immunohistochemistry may be useful in suggesting typical CNS WHO grade 1 meningiomas without the need for molecular analysis. We have defined meningioma stem cell signature via HARP phenomenon and identified CXCR4 with biological significance as being diagnostic target. IMPORTANCE OF THE STUDY: In addition to morphological evaluation, immunohistochemistry and genetic alteration increasingly incorporated into the diagnostic criteria for central nervous system (CNS) tumors. From the CNS WHO 5th edition onwards, epigenetic features including DNA methylation profiling, have also been adopted as diagnostic criteria. In this study, we induced epigenetic changes in meningioma cells and successfully promoted cancer stemness highlighting the potential importance of this approach for both meningioma research and meningioma diagnostic development. Furthermore, microarray analysis identified CXCR4 as a molecule consistently upregulated during stem cell induction across all three hydrogel conditions. Subsequent analysis revealed that CXCR4 immunohistochemistry may reflect the distribution of meningioma stem cells, supporting its potential utility as a diagnostic marker. By integrating basic experimental findings with histopathological evaluation of clinical specimens, this report will contribute to the advancement of meningioma research and diagnostic strategies.
• Astrocyte-Glioblastoma Stem Cell Interactions via Extracellular Vesicles Contribute to Distinct Vascular Structures.
  Yusuke Shirai; Masumi Tsuda; Lei Wang; Yoshitaka Oda; Hirokazu Sugizno; Zen-Ichi Tanei; Jian Ping Gong; Shinya Tanaka
  Pathology international, 76, 2, e70099, 2026年02月, ［国際誌］
  英語, 研究論文（学術雑誌）, Glioblastoma (GBM) is a highly malignant astrocytic tumor characterized by marked heterogeneity and therapeutic resistance. Cancer stem-like cells (CSCs) drive recurrence within specialized microenvironments, such as perivascular niches. Glioblastoma stem cells have been considered to interact with surrounding stromal cells, including astrocytes. To investigate these cell communications, we used a co-culture system of glioblastoma KMG4 cells and immortalized human astrocytes (NHA-TS) on hydrogels. Co-culture on hydrogel induced stemness- and epithelial-mesenchymal transition-related genes. Glioblastoma- and astrocyte-derived extracellular vesicles (EVs) were incorporated into reciprocal cells. NHA-TS-derived EVs regulated stemness of KMG4 cells, whereas KMG4-derived EVs increased expression of vascular development-related genes, such as THBS1 and ANGPT1 in astrocytes. Proteomic analysis identified COL1A1 and THBS1 in KMG4 and NHA-TS co-culture EVs. Spatial transcriptomic analysis of human GBM tissue demonstrated THBS1 and COL1A1 expression in perivascular regions. Culturing KMG4 cells on PNaSS gels upregulated pericyte-associated genes such as ACTA2, PDGFRB, HIGD1B. Within the perivascular microenvironment, EV-mediated interactions between glioblastoma cells and astrocytes support the induction of stemness and the differentiation of GBM cells toward a pericyte-like phenotype, promoting perivascular niche formation and microvascular proliferation. The hydrogel-based co-culture model thus provides a simple and effective platform for dissecting tumor-stroma communication in the glioblastoma microenvironment.
• Pitfall of the Diagnosis of Extramedullary Tumor: A Case of Intracranial Mesenchymal Tumor, FET::CREB Fusion‐Positive Occurring in an Atypical Clinical Setting
  Yoshitaka Oda; Yoshinobu Seo; Yosuke Masumoto; Taro Mori; Takeru kuwabara; Koki Ise; Yusuke Shirai; Hirokazu Sugino; Hiromi Okada; Zen‐ichi Tanei; Lei Wang; Bunsho Asayama; Shunsuke Sato; Yasuhiro Kikuchi; Masumi Tsuda; Yoshinao Oda; Shinya Tanaka
  Pathology International, Wiley, 2026年01月14日
  研究論文（学術雑誌）
• A non-spike nucleocapsid R204P mutation in SARS-CoV-2 Omicron XEC enhances inflammation and pathogenicity
  Shuhei Tsujino; Masumi Tsuda; Jumpei Ito; Sayaka Deguchi; Taha Y. Taha; Hesham Nasser; Lei Wang; Julia Rosecrans; Rigel Suzuki; Saori Suzuki; Kumiko Yoshimatsu; Melanie Ott; Terumasa Ikeda; Kazuo Takayama; Kei Sato; Shinya Tanaka; Tomokazu Tamura; Takasuke Fukuhara
  Cold Spring Harbor Laboratory, 2025年05月30日
  The global circulation of SARS-CoV-2 in human populations has driven the emergence of Omicron subvariants, which have become highly diversified through recombination. In late 2024, SARS-CoV-2 Omicron XEC variant emerged from the recombination of two JN.1 progeny, KS.1.1 and KP.3.3, and became predominant worldwide. Here, we investigated virological features of the XEC variant. Epidemic dynamics modeling suggested that spike substitutions in XEC mainly contribute to its increased viral fitness. Additionally, four licensed antivirals were effective against XEC. Although the fusogenicity of XEC spike is comparable to that of the JN.1 spike, the intrinsic pathogenicity of XEC in hamsters was significantly higher than that of JN.1. Notably, we found that the nucleocapsid R204P mutation of XEC enhanced inflammation through NF-κB activation. Recent studies suggest that the evolutionary potential of spike protein is reaching its limit. Indeed, our findings highlight the critical role of non-spike mutations in the future evolution of SARS-CoV-2.
• Distinct characteristics of brain metastasis in lung adenocarcinoma: development of high-confidence cell lines.
  Jintao He; Zen-Ichi Tanei; Dao-Sian Wu; Lei Wang; Yoshitaka Oda; Masumi Tsuda; Shinya Tanaka
  Acta neuropathologica communications, 13, 1, 109, 109, 2025年05月21日, ［国際誌］
  英語, 研究論文（学術雑誌）, Lung cancer is a leading cause of cancer-related deaths worldwide, with brain metastasis occurring in approximately 30-55% of patients, particularly in lung adenocarcinoma. Due to the challenges in obtaining genuine brain metastasis tumor cells, researchers commonly use nude mouse models to establish brain metastasis cell lines, though traditional methods have limitations such as high costs, lengthy timeframes, and the need for specialized imaging equipment. To address these issues, we developed an improved approach by performing low cell number circulating intracranial injections (500-4000 cells) in nude mice, successfully establishing the H1975-BM1, BM2, and BM3 cell lines. Through RNA sequencing and bioinformatics analyses, we identified transcriptomic differences among these cell lines, revealing that H1975-BM1 cells primarily exhibit stem cell function and migration characteristics, while H1975-BM3 cells display enhanced chemotaxis, cell adhesion, and cytokine secretion associated with interactions. Experimental validation, including Transwell assays, CCK8, cell adhesion assays, and subcutaneous tumor implantation in nude mice, further confirmed these findings, with H1975-BM3 forming larger tumors and a more pronounced secretion cystic cavity. In conclusion, our improved methodology successfully established high-confidence brain metastasis lung adenocarcinoma cell lines, elucidating distinct transcriptomic and functional characteristics at different stages of brain metastasis progression.
• A protein language model for exploring viral fitness landscapes
  Jumpei Ito; Adam Strange; Wei Liu; Gustav Joas; Spyros Lytras; Keita Matsuno; Naganori Nao; Hirofumi Sawa; Keita Mizuma; Isshu Kojima; Jingshu Li; Tomoya Tsubo; Shinya Tanaka; Masumi Tsuda; Lei Wang; Yoshikata Oda; Zannatul Ferdous; Kenji Shishido; Takasuke Fukuhara; Tomokazu Tamura; Rigel Suzuki; Saori Suzuki; Shuhei Tsujino; Hayato Ito; Yu Kaku; Naoko Misawa; Arnon Plianchaisuk; Ziyi Guo; Alfredo A. Hinay; Kaoru Usui; Wilaiporn Saikruang; Keiya Uriu; Yusuke Kosugi; Shigeru Fujita; Jarel Elgin M.Tolentino; Luo Chen; Lin Pan; Wenye Li; Mai Suganami; Mika Chiba; Ryo Yoshimura; Kyoko Yasuda; Keiko Iida; Naomi Ohsumi; Shiho Tanaka; Kaho Okumura; Kazuhisa Yoshimura; Kenji Sadamas; Mami Nagashima; Hiroyuki Asakura; Isao Yoshida; So Nakagawa; Akifumi Takaori-Kondo; Kotaro Shirakawa; Kayoko Nagata; Ryosuke Nomura; Yoshihito Horisawa; Yusuke Tashiro; Yugo Kawai; Kazuo Takayama; Rina Hashimoto; Sayaka Deguchi; Yukio Watanabe; Yoshitaka Nakata; Hiroki Futatsusako; Ayaka Sakamoto; Naoko Yasuhara; Takao Hashiguchi; Tateki Suzuki; Kanako Kimura; Jiei Sasaki; Yukari Nakajima; Hisano Yajima; Takashi Irie; Ryoko Kawabata; Kaori Sasaki-Tabata; Terumasa Ikeda; Hesham Nasse; Ryo Shimizu; MST Monira Begum; Michael Jonathan; Yuka Mugita; Sharee Leong; Otowa Takahashi; Kimiko Ichihara; Takamasa Ueno; Chihiro Motozono; Mako Toyoda; Akatsuki Saito; Maya Shofa; Yuki Shibatani; Tomoko Nishiuchi; Jiri Zahradni; Prokopios Andrikopoulos; Miguel Padilla-Blanco; Aditi Konar; Kei Sato
  Nature Communications, 16, 1, Springer Science and Business Media LLC, 2025年05月13日, ［査読有り］
  研究論文（学術雑誌）
• 側脳室に発生した脂肪化細胞を伴う中枢性神経細胞腫の一例
  桑原 傑; 小田 義崇; 藤原 雄介; 伊勢 昂生; 王 磊; 種井 善一; 津田 真寿美; 田中 伸哉
  Brain Tumor Pathology, 42, Suppl., 128, 128, 日本脳腫瘍病理学会, 2025年05月
  英語
• Mechanochemistry-Induced Universal Hydrogel Surface Modification for Orientation and Enhanced Differentiation of Skeletal Muscle Myoblasts
  Yuheng Nie; Qifeng Mu; Yanpeng Sun; Zannatul Ferdous; Lei Wang; Cewen Chen; Tasuku Nakajima; Jian Ping Gong; Shinya Tanaka; Masumi Tsuda
  ACS Applied Bio Materials, 8, 4, 3144, 3155, American Chemical Society (ACS), 2025年03月19日
  研究論文（学術雑誌）
• 血管周囲ニッシェに潜伏する膠芽腫幹細胞を標的とした治療戦略(Treatment strategy targeting glioblastoma stem cells latent in the perivascular niche)
  津田 真寿美; 高村 敦子; 大西 健太; 王 磊; 小田 義崇; 田中 伸哉
  日本病理学会会誌, 114, 1, 295, 295, (一社)日本病理学会, 2025年03月
  英語
• 非腫瘍性神経疾患の病理学的解析 北大における病理解剖と神経病理研究(Pathological analysis of non-tumor neurological diseases Autopsy and research of the nervous system at Hokkaido University)
  種井 善一; 小田 義崇; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 114, 1, 189, 189, (一社)日本病理学会, 2025年03月
  英語
• 高機能ハイドロゲルを用いた白血病幹細胞の創出(Analysis for of synthelic polymer hydrogel-mediated generation of leuklamia stem cell)
  小田 義崇; 澤井 彩織; 齋藤 祐介; 桑原 傑; 王 磊; 種井 善一; 津田 真寿美; 真部 淳; ぐん 剣萍; 田中 伸哉
  日本病理学会会誌, 114, 1, 280, 280, (一社)日本病理学会, 2025年03月
  英語
• AIによる悪性脳腫瘍分類 基盤モデルの転移学習戦略比較(AI-based Brain Tumor Classification: Comparing Transfer Learning Strategies for Foundation Models)
  遠田 建; 小田 義崇; 種井 善一; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 114, 1, 281, 281, (一社)日本病理学会, 2025年03月
  英語
• 膠芽腫の単一細胞分子分類と腫瘍関連マクロファージとの局在に関わる空間トランスクリプトーム解析(Spatial transcriptomics of macrophages and single cell molecular classification in glioblastoma)
  伊勢 昂生; 種井 善一; 桑原 傑; 遠田 建; 白井 裕介; He Jinto; 小田 義崇; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 114, 1, 294, 294, (一社)日本病理学会, 2025年03月
  英語
• 腫瘍微小環境における膠芽腫幹細胞と星状膠細胞の相互作用の検討(Analysis of interaction between glioblastoma stem cells and astrocytes in tumor microenvironment)
  白井 裕介; 津田 真寿美; 王 磊; 小田 義崇; 種井 善一; 田中 伸哉
  日本病理学会会誌, 114, 1, 406, 406, (一社)日本病理学会, 2025年03月
  英語
• 低体温症から救命後、急性呼吸窮迫症候群(ARDS)を発症し、死亡した一解剖例
  森口 いる麻; 伊勢 昴生; 白神 美織; 中村 海人; 小田 義崇; 種井 善一; 王 磊; 津田 真寿美; 太田 聡; 田中 伸哉
  日本病理学会会誌, 114, 1, 451, 451, (一社)日本病理学会, 2025年03月
  日本語
• 高異軽度子宮内膜間質肉腫の1解剖例
  小泉 悠; 白井 祐介; 西村 真唯; 小田 義崇; 種井 善一; 王 磊; 津田 真寿美; 和田 真一郎; 太田 聡; 田中 伸哉
  日本病理学会会誌, 114, 1, 453, 453, (一社)日本病理学会, 2025年03月
  日本語
• 44歳の脊髄小脳変性症(マシャドジョセフ病)の一解剖例
  張 一夫; 伊勢 昴生; 白井 慎一; 小田 義崇; 種井 善一; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 114, 1, 455, 455, (一社)日本病理学会, 2025年03月
  日本語
• Hydrogel PCDME creates pancreatic cancer stem cells in OXPHOS metabolic state with TXNIP elevation
  Yuma Aoki; Lei Wang; Masumi Tsuda; Yusuke Saito; Takenori Kubota; Yoshitaka Oda; Satoshi Hirano; Jian Ping Gong; Shinya Tanaka
  Biochemical and Biophysical Research Communications, 751, 151416, 151416, Elsevier BV, 2025年03月
  研究論文（学術雑誌）
• Evolution of BA.2.86 to JN.1 reveals functional changes in non-structural viral proteins are required for fitness of SARS-CoV-2
  Shuhei Tsujino; Masumi Tsuda; Naganori Nao; Kaho Okumura; Lei Wang; Yoshitaka Oda; Yume Mimura; Jingshu Li; Rina Hashimoto; Yasufumi Matsumura; Rigel Suzuki; Saori Suzuki; Kumiko Yoshimatsu; Miki Nagao; Jumpei Ito; Kazuo Takayama; Kei Sato; Keita Matsuno; Tomokazu Tamura; Shinya Tanaka; Takasuke Fukuhara
  Cold Spring Harbor Laboratory, 2025年02月19日
  ABSTRACT
  
  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19), is still circulating among humans, leading to the continuous evolution. SARS-CoV-2 Omicron JN.1 evolved from a distinct SARS-CoV-2 lineage, BA.2.86, spread rapidly worldwide. It is unclear why BA.2.86 did not become dominant and was quickly replaced by JN.1, which possesses one amino acid substitution in the spike protein (S:L455S) and two in the non-spike proteins NSP6 and ORF7b (NSP6:R252K and ORF7b:F19L) compared to BA.2.86. Here, we utilized recombinant viruses to elucidate the impact of these mutations on the virological characteristics of JN.1. We found that the mutation in the spike attenuated viral replication, but the non-spike mutations enhanced replication, suggesting the mutations in the non-spike proteins compensate for the one in the spike to improve viral fitness, as the mutations in the spike contribute to further immune evasion. Our findings suggest that functional changes in both the spike and non-spike proteins are necessary in the evolution of SARS-CoV-2 to enable evasion of adaptive immunity within the human population while sustaining replication.
  
  IMPORTANCE
  
  Because the spike protein is strongly associated with certain virological properties of SARS-CoV-2, such as immune evasion and infectivity, most previous studies on SARS-CoV-2 variants have focused on spike protein mutations. However, the non-spike proteins also contribute to infectivity, as observed throughout the evolution of Omicron subvariants. In this study, we demonstrate a “trade-off” strategy in SARS-CoV-2 Omicron JN.1 in which the reduced infectivity caused by spike mutation is compensated by non-spike mutations. Our results provide insight into the evolutionary scenario of the emerging virus in the human population.
• SLC13A5 plays an essential role in the energy shift to oxidative phosphorylation in cisplatin-resistant mesothelioma stem cells.
  Marie Kato-Shinomiya; Hirokazu Sugino; Lei Wang; Yusuke Saito; Jintao He; Zen-Ichi Tanei; Yoshitaka Oda; Satoshi Tanikawa; Mishie Tanino; Jian Ping Gong; Masumi Tsuda; Shinya Tanaka
  Pathology international, 2025年02月06日, ［国際誌］
  英語, 研究論文（学術雑誌）, Mesothelioma is a highly aggressive tumor affecting an increasing number of patients worldwide. Owing to the poor clinical outcomes associated with current therapies, the development of novel therapies that target cancer stem cells (CSCs) is desirable. Here, we examined the applicability of our previously established hydrogel-based rapid CSC generation method to human mesothelioma cell lines and further analyzed the characteristics of the induced mesothelioma stem cell (MesoSC) -like cells. Human mesothelioma cell lines cultured on hydrogels presented increased expression of pan-stem cell markers and acquired spheroid formation and early tumorigenicity, suggesting that MesoSC-like cells are highly malignant. Microarray analysis demonstrated that the expression of SLC13A5, a citrate transporter involved in TCA cycle, was significantly induced in the resulting MesoSC-like cells. The overexpression of SLC13A5 resulted in a metabolic shift toward oxidative phosphorylation, increased phosphorylation of ERK and YAP, and increased SOX2 expression, leading to increased cisplatin resistance. scRNA-seq database analysis revealed that clinical mesothelioma samples contained a small number of SLC13A5-expressing cells. Our findings suggest that the hydrogel-based CSC generation method is also effective for human mesothelioma cells and that SLC13A5 may contribute to MesoSC survival. The new properties of MesoSCs revealed in this study may provide clues for establishing future treatments.
• Establishment of a novel method for differentiating into dopaminergic neurons using charged hydrogels.
  Bin Fan; Satoshi Tanikawa; Lei Wang; Takayuki Nonoyama; Yashitaka Oda; Zen-Ichi Tanei; Jian Ping Gong; Masumi Tsuda; Shinya Tanaka
  Biochemical and biophysical research communications, 747, 151280, 151280, 2025年02月02日, ［国際誌］
  英語, 研究論文（学術雑誌）, Parkinson's disease (PD) is a neurodegenerative disease primarily affecting the central nervous system and impacting both the motor system and non-motor systems. Although administration of L-DOPA is effective, it is not a fundamental treatment and has side effects such as diurnal fluctuation and dyskinesia, highlighting the need for new treatment methods. There is a growing interest in dopaminergic neuron transplantation as a potential treatment. Dopaminergic neurons derived from pluripotent stem (iPS) cells provide a valuable source for transplantation therapies. Developing an efficient method to differentiate iPS cells into dopaminergic cells is essential for cell transplantation therapy. While Cell differentiation is typically controlled by the addition of specific reagents, the physical characteristics of culture substrate, especially in the charge and stiffness, are also crucial factors in regulating differentiation. In this research, we show that two newly developed electrically charged polymeric hydrogels composed of cationic (C) and anionic (A) monomers inratio of 1-9 and 2 to 8 can significantly promote Dopaminergic neuron differentiation. Our findings emphasize the importance of culture substrates in effective dopaminergic cell differentiation.
• Transfer Learning Strategies for Pathological Foundation Models: A Systematic Evaluation in Brain Tumor Classification.
  Ken Enda; Yoshitaka Oda; Zen-ichi Tanei; Wang Lei; Masumi Tsuda; Takahiro Ogawa 0001; Shinya Tanaka
  CoRR, abs/2501.11014, 2025年01月
  研究論文（学術雑誌）
• Tumor-mimetic hydrogel stiffness regulates cancer stemness properties in H-Ras-transformed cancer model cells
  Yanpeng Sun; Yuheng Nie; Lei Wang; Jian Ping Gong; Shinya Tanaka; Masumi Tsuda
  Biochemical and Biophysical Research Communications, 743, 151163, 151163, Elsevier BV, 2025年01月
  研究論文（学術雑誌）
• Molecular and structural insights into SARS-CoV-2 evolution: from BA.2 to XBB subvariants
  Hisano Yajima; Tomo Nomai; Kaho Okumura; Katsumi Maenaka; Jumpei Ito; Takao Hashiguchi; Kei Sato; Keita Matsuno; Naganori Nao; Hirofumi Sawa; Keita Mizuma; Jingshu Li; Izumi Kida; Yume Mimura; Yuma Ohari; Shinya Tanaka; Masumi Tsuda; Lei Wang; Yoshikata Oda; Zannatul Ferdous; Kenji Shishido; Hiromi Mohri; Miki Iida; Takasuke Fukuhara; Tomokazu Tamura; Rigel Suzuki; Saori Suzuki; Shuhei Tsujino; Hayato Ito; Yu Kaku; Naoko Misawa; Arnon Plianchaisuk; Ziyi Guo; Alfredo A. Hinay; Kaoru Usui; Wilaiporn Saikruang; Spyridon Lytras; Keiya Uriu; Ryo Yoshimura; Shusuke Kawakubo; Luca Nishumura; Yusuke Kosugi; Shigeru Fujita; Jarel Elgin M.Tolentino; Luo Chen; Lin Pan; Wenye Li; Maximilian Stanley Yo; Kio Horinaka; Mai Suganami; Mika Chiba; Kyoko Yasuda; Keiko Iida; Adam Patrick Strange; Naomi Ohsumi; Shiho Tanaka; Eiko Ogawa; Tsuki Fukuda; Rina Osujo; Kazuhisa Yoshimura; Kenji Sadamas; Mami Nagashima; Hiroyuki Asakura; Isao Yoshida; So Nakagawa; Kazuo Takayama; Rina Hashimoto; Sayaka Deguchi; Yukio Watanabe; Yoshitaka Nakata; Hiroki Futatsusako; Ayaka Sakamoto; Naoko Yasuhara; Tateki Suzuki; Kanako Kimura; Jiei Sasaki; Yukari Nakajima; Takashi Irie; Ryoko Kawabata; Kaori Sasaki-Tabata; Terumasa Ikeda; Hesham Nasser; Ryo Shimizu; Mst Monira Begum; Michael Jonathan; Yuka Mugita; Sharee Leong; Otowa Takahashi; Takamasa Ueno; Chihiro Motozono; Mako Toyoda; Akatsuki Saito; Anon Kosaka; Miki Kawano; Natsumi Matsubara; Tomoko Nishiuchi; Jiri Zahradnik; Prokopios Andrikopoulos; Miguel Padilla-Blanco; Aditi Konar
  mBio, 15, 10, American Society for Microbiology, 2024年10月16日
  研究論文（学術雑誌）, ABSTRACT
  
  Due to the incessant emergence of various SARS-CoV-2 variants with enhanced fitness in the human population, controlling the COVID-19 pandemic has been challenging. Understanding how the virus enhances its fitness during a pandemic could offer valuable insights for more effective control of viral epidemics. In this manuscript, we review the evolution of SARS-CoV-2 from early 2022 to the end of 2023—from Omicron BA.2 to XBB descendants. Focusing on viral evolution during this period, we provide concrete examples that SARS-CoV-2 has increased its fitness by enhancing several functions of the spike (S) protein, including its binding affinity to the ACE2 receptor and its ability to evade humoral immunity. Furthermore, we explore how specific mutations modify these functions of the S protein through structural alterations. This review provides evolutionary, molecular, and structural insights into how SARS-CoV-2 has increased its fitness and repeatedly caused epidemic surges during the pandemic.
• 微小血管増生ニッシェに潜在するグリオーマ幹細胞を標的とした治療戦略(Treatment strategy targeting glioma stem cells latent in the microvascular proliferation niche)
  津田 真寿美; 王 磊; 小田 義崇; 田中 伸哉; 田中 伸哉
  日本癌学会総会記事, 83回, E, 1003, (一社)日本癌学会, 2024年09月
  英語
• ハイドロゲル上で誘導された膀胱癌幹細胞の特徴と標的治療の探索(Characteristics and targeted therapeutic prospects of bladder cancer stem cells induced on hydrogels)
  王 磊; 津田 真寿美; 小田 義崇; 田中 伸哉
  日本癌学会総会記事, 83回, P, 1102, (一社)日本癌学会, 2024年09月
  英語
• Virological characteristics of the SARS-CoV-2 Omicron EG.5.1 variant.
  Shuhei Tsujino; Sayaka Deguchi; Tomo Nomai; Miguel Padilla-Blanco; Arnon Plianchaisuk; Lei Wang; Mst Monira Begum; Keiya Uriu; Keita Mizuma; Naganori Nao; Isshu Kojima; Tomoya Tsubo; Jingshu Li; Yasufumi Matsumura; Miki Nagao; Yoshitaka Oda; Masumi Tsuda; Yuki Anraku; Shunsuke Kita; Hisano Yajima; Kaori Sasaki-Tabata; Ziyi Guo; Alfredo A Hinay Jr; Kumiko Yoshimatsu; Yuki Yamamoto; Tetsuharu Nagamoto; Hiroyuki Asakura; Mami Nagashima; Kenji Sadamasu; Kazuhisa Yoshimura; Hesham Nasser; Michael Jonathan; Olivia Putri; Yoonjin Kim; Luo Chen; Rigel Suzuki; Tomokazu Tamura; Katsumi Maenaka; Takashi Irie; Keita Matsuno; Shinya Tanaka; Jumpei Ito; Terumasa Ikeda; Kazuo Takayama; Jiri Zahradnik; Takao Hashiguchi; Takasuke Fukuhara; Kei Sato
  Microbiology and immunology, 2024年07月04日, ［国際誌］
  英語, 研究論文（学術雑誌）, In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population.
• Involvement of SARS-CoV-2 accessory proteins in immunopathogenesis.
  Hayato Ito; Tomokazu Tamura; Lei Wang; Kento Mori; Masumi Tsuda; Rigel Suzuki; Saori Suzuki; Kumiko Yoshimatsu; Shinya Tanaka; Takasuke Fukuhara
  Microbiology and immunology, 68, 7, 237, 247, 2024年07月, ［国際誌］
  英語, 研究論文（学術雑誌）, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the largest single-stranded RNA virus known to date. Its genome contains multiple accessory protein genes that act against host immune responses but are not required for progeny virus production. The functions of the accessory proteins in the viral life cycle have been examined, but their involvement in viral pathogenicity remains unclear. Here, we investigated the roles of the accessory proteins in viral immunopathogenicity. To this end, recombinant SARS-CoV-2 possessing nonsense mutations in the seven accessory protein open reading frames (ORFs) (ORF3a, ORF3b, ORF6, ORF7a, ORF8, ORF9b, and ORF10) was de novo generated using an early pandemic SARS-CoV-2 strain as a backbone. We confirmed that the resultant virus (termed ORF3-10 KO) did not express accessory proteins in infected cells and retained the desired mutations in the viral genome. In cell culture, the ORF3-10 KO virus exhibited similar virus growth kinetics as the parental virus. In hamsters, ORF3-10 KO virus infection resulted in mild weight loss and reduced viral replication in the oral cavity and lung tissue. ORF3-10 KO virus infection led to mild inflammation, indicating that an inability to evade innate immune sensing because of a lack of accessory proteins impairs virus growth in vivo and results in quick elimination from the body. Overall, we showed that SARS-CoV-2 accessory proteins are involved in immunopathogenicity.
• Virological characteristics of a SARS-CoV-2-related bat coronavirus, BANAL-20-236.
  Shigeru Fujita; Arnon Plianchaisuk; Sayaka Deguchi; Hayato Ito; Naganori Nao; Lei Wang; Hesham Nasser; Tomokazu Tamura; Izumi Kimura; Yukie Kashima; Rigel Suzuki; Saori Suzuki; Izumi Kida; Masumi Tsuda; Yoshitaka Oda; Rina Hashimoto; Yukio Watanabe; Keiya Uriu; Daichi Yamasoba; Ziyi Guo; Alfredo A Hinay Jr; Yusuke Kosugi; Luo Chen; Lin Pan; Yu Kaku; Hin Chu; Flora Donati; Sarah Temmam; Marc Eloit; Yuki Yamamoto; Tetsuharu Nagamoto; Hiroyuki Asakura; Mami Nagashima; Kenji Sadamasu; Kazuhisa Yoshimura; Yutaka Suzuki; Jumpei Ito; Terumasa Ikeda; Shinya Tanaka; Keita Matsuno; Takasuke Fukuhara; Kazuo Takayama; Kei Sato
  EBioMedicine, 104, 105181, 105181, 2024年06月, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Although several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences in virological characteristics between SARS-CoV-2 and SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat and was found to lack a furin cleavage site (FCS) in the spike (S) protein. The comparison of its virological characteristics with FCS-deleted SARS-CoV-2 (SC2ΔFCS) has not been conducted yet. METHODS: We prepared human induced pluripotent stem cell (iPSC)-derived airway and lung epithelial cells and colon organoids as human organ-relevant models. B236, SARS-CoV-2, and artificially generated SC2ΔFCS were used for viral experiments. To investigate the pathogenicity of B236 in vivo, we conducted intranasal infection experiments in hamsters. FINDINGS: In human iPSC-derived airway epithelial cells, the growth of B236 was significantly lower than that of the SC2ΔFCS. A fusion assay showed that the B236 and SC2ΔFCS S proteins were less fusogenic than the SARS-CoV-2 S protein. The infection experiment in hamsters showed that B236 was less pathogenic than SARS-CoV-2 and even SC2ΔFCS. Interestingly, in human colon organoids, the growth of B236 was significantly greater than that of SARS-CoV-2. INTERPRETATION: Compared to SARS-CoV-2, we demonstrated that B236 exhibited a tropism toward intestinal cells rather than respiratory cells. Our results are consistent with a previous report showing that B236 is enterotropic in macaques. Altogether, our report strengthens the assumption that SC2r-CoVs in horseshoe bats replicate primarily in the intestinal tissues rather than respiratory tissues. FUNDING: This study was supported in part by AMED ASPIRE (JP23jf0126002, to Keita Matsuno, Kazuo Takayama, and Kei Sato); AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVReD) (JP223fa627005h0001, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); The Naito Foundation (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation (to Tomokazu Tamura); and Mitsubishi Foundation (to Kei Sato).
• 希少がん診断における病理・細胞診 脳腫瘍の細胞像と病理像
  種井 善一; 小田 義崇; 王 磊; 津田 真寿美; 田中 伸哉
  日本臨床細胞学会雑誌, 63, Suppl.1, 104, 104, (公社)日本臨床細胞学会, 2024年05月
  日本語
• 希少がん診断における病理・細胞診 脳腫瘍の細胞像と病理像
  種井 善一; 小田 義崇; 王 磊; 津田 真寿美; 田中 伸哉
  日本臨床細胞学会雑誌, 63, Suppl.1, 104, 104, (公社)日本臨床細胞学会, 2024年05月
  日本語
• 脳腫瘍の分子診断と治療2 バイオマテリアルを用いたグリオーマ幹細胞ニッシェの構築
  津田 真寿美; 王 磊; 小田 義崇; 種井 善一; 田中 伸哉
  Brain Tumor Pathology, 41, Suppl., 101, 101, 日本脳腫瘍病理学会, 2024年05月
  日本語
• Virological characteristics of the SARS-CoV-2 BA.2.86 variant.
  Tomokazu Tamura; Keita Mizuma; Hesham Nasser; Sayaka Deguchi; Miguel Padilla-Blanco; Yoshitaka Oda; Keiya Uriu; Jarel E M Tolentino; Shuhei Tsujino; Rigel Suzuki; Isshu Kojima; Naganori Nao; Ryo Shimizu; Lei Wang; Masumi Tsuda; Michael Jonathan; Yusuke Kosugi; Ziyi Guo; Alfredo A Hinay Jr; Olivia Putri; Yoonjin Kim; Yuri L Tanaka; Hiroyuki Asakura; Mami Nagashima; Kenji Sadamasu; Kazuhisa Yoshimura; Akatsuki Saito; Jumpei Ito; Takashi Irie; Shinya Tanaka; Jiri Zahradnik; Terumasa Ikeda; Kazuo Takayama; Keita Matsuno; Takasuke Fukuhara; Kei Sato
  Cell host & microbe, 32, 2, 170, 180, 2024年02月14日, ［国際誌］
  英語, 研究論文（学術雑誌）, In late 2023, several SARS-CoV-2 XBB descendants, notably EG.5.1, were predominant worldwide. However, a distinct SARS-CoV-2 lineage, the BA.2.86 variant, also emerged. BA.2.86 is phylogenetically distinct from other Omicron sublineages, accumulating over 30 amino acid mutations in its spike protein. Here, we examined the virological characteristics of the BA.2.86 variant. Our epidemic dynamics modeling suggested that the relative reproduction number of BA.2.86 is significantly higher than that of EG.5.1. Additionally, four clinically available antivirals were effective against BA.2.86. Although the fusogenicity of BA.2.86 spike is similar to that of the parental BA.2 spike, the intrinsic pathogenicity of BA.2.86 in hamsters was significantly lower than that of BA.2. Since the growth kinetics of BA.2.86 are significantly lower than those of BA.2 both in vitro and in vivo, the attenuated pathogenicity of BA.2.86 is likely due to its decreased replication capacity. These findings uncover the features of BA.2.86, providing insights for control and treatment.
• ハイドロゲルを用いた新規治療耐性細胞株の樹立(Establishment of novel treatment-resistant cell lines using hydrogel)
  王 磊; 窪田 武哲; 津田 真寿美; 小田 義崇; 平野 聡; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 113, 1, 401, 401, (一社)日本病理学会, 2024年02月
  英語
• ハムスター肺炎モデルを用いたSARS-CoV-2肺炎の病理組織学的解析(Histopathological analysis of hamster SARS-CoV-2 pneumonia model)
  小田 義崇; 津田 真寿美; 王 磊; 種井 善一; 福原 崇介; 佐藤 佳; 田中 伸哉
  日本病理学会会誌, 113, 1, 301, 301, (一社)日本病理学会, 2024年02月
  英語
• マントルリンパ腫とびまん性大細胞型B細胞性リンパ腫のdiscordant lymphomaの一解剖例(An autopsy case of discordant lymphoma: mantle cell lymphoma and diffuse large B-cell lymphoma)
  岸浪 建; 小田 義崇; 王 磊; 江端 浩; 加藤 万里絵; 種井 善一; 津田 真寿美; 宮城島 拓人; 田中 伸哉
  日本病理学会会誌, 113, 1, 453, 453, (一社)日本病理学会, 2024年02月
  英語
• 慢性肺血栓塞栓症の二剖検例
  岸本 佳子; 種井 善一; 青木 健志; 棒田 浩基; 小田 義崇; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 113, 1, 468, 468, (一社)日本病理学会, 2024年02月
  日本語
• 14年後に再発したBRAF V600E変異を有するlow-grade gliomaの1例
  黒田 花音; 小田 義崇; 岡本 迪成; 村木 岳史; 種井 善一; 王 磊; 津田 真寿美; 高阪 真路; 西原 広史; 田中 伸哉
  日本病理学会会誌, 113, 1, 482, 482, (一社)日本病理学会, 2024年02月
  日本語
• 左同名半盲をきたした頭蓋内腫瘍の一例
  長野 七海; 種井 善一; 福島 大地; 小田 義崇; 王 磊; 津田 真寿美; 山村 明範; 田中 伸哉
  日本病理学会会誌, 113, 1, 482, 482, (一社)日本病理学会, 2024年02月
  日本語
• BRAF p.V600E変異を有するHigh-grade Gliomaの病理学的研究
  京野 里虹; 種井 善一; 伊師 雪友; 小田 義崇; 王 磊; 津田 真寿美; 佐藤 憲市; 寺坂 俊介; 田中 伸哉
  日本病理学会会誌, 113, 1, 482, 482, (一社)日本病理学会, 2024年02月
  日本語
• MELAS様症状とMT-ATP6 m.8639T>C変異を伴う71歳男性の一剖検例
  戸田 壮太郎; 小田 義崇; 種井 善一; 王 磊; 大森 優子; 石田 雄介; 津田 真寿美; 松岡 健; 田中 伸哉
  日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
  日本語
• 30代男性のアミロイドアンギオパチーの病理像
  馬詰 知佐; 種井 善一; 小田 義崇; 藤井 恭子; 王 磊; 津田 真寿美; 山口 大志; 中村 博彦; 田中 伸哉
  日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
  日本語
• FFPE検体の質量分析による交感神経節のレビー小体関連分子の探索
  宮本 裕也; 種井 善一; 小田 義崇; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
  日本語
• Nerve sheath myxomaのプロテオミクス解析による免疫組織化学マーカー探索
  鍵谷 豪太; 種井 善一; 小田 義崇; 王 磊; 津田 真寿美; 飛騨 一利; 田中 伸哉
  日本病理学会会誌, 113, 1, 483, 483, (一社)日本病理学会, 2024年02月
  日本語
• Determination of the factors responsible for the tropism of SARS-CoV-2-related bat coronaviruses to Rhinolophus bat ACE2
  Shigeru Fujita; Yusuke Kosugi; Izumi Kimura; Kenzo Tokunaga; Jumpei Ito; Kei Sato; Keita Matsuno; Naganori Nao; Hirofumi Sawa; Shinya Tanaka; Masumi Tsuda; Lei Wang; Yoshikata Oda; Zannatul Ferdous; Kenji Shishido; Takasuke Fukuhara; Tomokazu Tamura; Rigel Suzuki; Saori Suzuki; Hayato Ito; Yu Kaku; Naoko Misawa; Arnon Plianchaisuk; Ziyi Guo; Alfredo A. Hinay; Keiya Uriu; Jarel Elgin M. Tolentino; Luo Chen; Lin Pan; Mai Suganami; Mika Chiba; Ryo Yoshimura; Kyoko Yasuda; Keiko Iida; Naomi Ohsumi; Adam P. Strange; Shiho Tanaka; Kazuhisa Yoshimura; Kenji Sadamasu; Mami Nagashima; Hiroyuki Asakura; Isao Yoshida; So Nakagawa; Akifumi Takaori-Kondo; Kayoko Nagata; Ryosuke Nomura; Yoshihito Horisawa; Yusuke Tashiro; Yugo Kawai; Kazuo Takayama; Rina Hashimoto; Sayaka Deguchi; Yukio Watanabe; Ayaka Sakamoto; Naoko Yasuhara; Takao Hashiguchi; Tateki Suzuki; Kanako Kimura; Jiei Sasaki; Yukari Nakajima; Hisano Yajima; Takashi Irie; Ryoko Kawabata; Kaori Tabata; Terumasa Ikeda; Hesham Nasser; Ryo Shimizu; M. S. T. Monira Begum; Michael Jonathan; Yuka Mugita; Otowa Takahashi; Kimiko Ichihara; Chihiro Motozono; Takamasa Ueno; Mako Toyoda; Akatsuki Saito; Maya Shofa; Yuki Shibatani; Tomoko Nishiuchi; Kotaro Shirakawa
  Journal of Virology, 97, 10, 2023年10月31日
  研究論文（学術雑誌）
• Akaluc bioluminescence offers superior sensitivity to trackin vivodynamics of SARS-CoV-2 infection
  Tomokazu Tamura; Hayato Ito; Shiho Torii; Lei Wang; Rigel Suzuki; Shuhei Tusjino; Akifumi Kamiyama; Yoshitaka Oda; Yuhei Morioka; Saori Suzuki; Kotaro Shirakawa; Kei Sato; Kumiko Yoshimatsu; Yoshiharu Matsuura; Satoshi Iwano; Shinya Tanaka; Takasuke Fukuhara
  Cold Spring Harbor Laboratory, 2023年10月13日
  Summary
  
  Monitoringin vivoviral dynamics can improve our understanding of pathogenicity and tissue tropism. For positive-sense, single-stranded RNA viruses, several studies have attempted to monitor viral kineticsin vivousing reporter genomes. The application of such recombinant viruses can be limited by challenges in accommodating bioluminescent reporter genes in the viral genome. Conventional luminescence also exhibits relatively low tissue permeability and thus less sensitivity for visualizationin vivo. Here we show that unlike NanoLuc bioluminescence, the improved method, termed AkaBLI, allows visualization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Syrian hamsters. By successfully incorporating a codon-optimized Akaluc luciferase gene into the SARS-CoV-2 genome, we visualizedin vivoinfection, including the tissue-specific differences associated with particular variants. Additionally, we could evaluate the efficacy of neutralizing antibodies and mRNA vaccination by monitoring changes in Akaluc signals. Overall, AkaBLI is an effective technology for monitoring viral dynamics in live animals.
• SARS-CoV-2オミクロン株におけるハムスター肺炎モデルの病理組織学的解析
  小田 義崇; 津田 真寿美; 王 磊; 種井 善一; 福原 崇介; 佐藤 佳; 田中 伸哉
  日本病理学会会誌, 112, 2, 132, 132, (一社)日本病理学会, 2023年10月
  日本語
• ハイドロゲルPCDMEは、TXNIP上昇を伴うOXPHOS代謝状態の膵臓癌幹細胞を誘導する(Hydrogel PCDME creates pancreatic cancer stem cells in OXPHOS metabolic state with TXNIP elevation)
  王 磊; 青木 佑磨; 津田 真寿美; 小田 義崇; 田中 伸哉
  日本癌学会総会記事, 82回, 1361, 1361, (一社)日本癌学会, 2023年09月
  英語
• Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant.
  Jumpei Ito; Rigel Suzuki; Keiya Uriu; Yukari Itakura; Jiri Zahradnik; Kanako Terakado Kimura; Sayaka Deguchi; Lei Wang; Spyros Lytras; Tomokazu Tamura; Izumi Kida; Hesham Nasser; Maya Shofa; Mst Monira Begum; Masumi Tsuda; Yoshitaka Oda; Tateki Suzuki; Jiei Sasaki; Kaori Sasaki-Tabata; Shigeru Fujita; Kumiko Yoshimatsu; Hayato Ito; Naganori Nao; Hiroyuki Asakura; Mami Nagashima; Kenji Sadamasu; Kazuhisa Yoshimura; Yuki Yamamoto; Tetsuharu Nagamoto; Jin Kuramochi; Gideon Schreiber; Akatsuki Saito; Keita Matsuno; Kazuo Takayama; Takao Hashiguchi; Shinya Tanaka; Takasuke Fukuhara; Terumasa Ikeda; Kei Sato
  Nature communications, 14, 1, 2671, 2671, 2023年05月11日, ［国際誌］
  英語, 研究論文（学術雑誌）, In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.
• てんかんを発症した72歳女性の右側頭葉内側部病変
  種井 善一; 浅野目 卓; 小野 裕介; 小田 義崇; 王 磊; 津田 真寿美; 佐藤 憲市; 水上 裕輔; 田中 伸哉
  Brain Tumor Pathology, 40, Suppl., 126, 126, 日本脳腫瘍病理学会, 2023年05月
  日本語
• 脳腫瘍に対する病理研究者としての克服戦略 ハイドロゲルによる髄膜腫幹細胞の探索(Strategies for overcoming the brain tumors presented by pathology researchers Search for meningioma stem cells using hydrogel)
  小田 義崇; 津田 真寿美; 湯澤 明夏; 王 磊; 鈴鹿 淳; ハビバ・ウンマ; 種井 善一; モーウリン・クリスチアン; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 112, 1, 184, 184, (一社)日本病理学会, 2023年03月
  英語
• 72歳女性のMultinodular and Vacuolating Neuronal Tumor of the cerebrumの1例
  寺島 祐樹; 種井 善一; 浅野目 卓; 黒田 花音; 小田 義崇; 谷川 聖; 王 磊; 津田 真寿美; 佐藤 憲市; 田中 伸哉
  日本病理学会会誌, 112, 1, 375, 375, (一社)日本病理学会, 2023年03月
  日本語
• 電子顕微鏡的検討を行ったラブドイド髄膜腫の一症例
  戸田 壮太郎; 種井 善一; 京野 里虹; 寺島 祐樹; 谷川 聖; 小田 義崇; 王 磊; 津田 真寿美; 瀬尾 善宣; 田中 伸哉
  日本病理学会会誌, 112, 1, 380, 380, (一社)日本病理学会, 2023年03月
  日本語
• 髄膜腫の骨化におけるEpithelial-mesenchymal transitionの関与についての検討
  京野 里虹; 種井 善一; 寺島 祐樹; 小田 義崇; 谷川 聖; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 112, 1, 381, 381, (一社)日本病理学会, 2023年03月
  日本語
• FFPE検体の質量分析による肺小細胞癌の脳転移関連分子の解析
  江端 美織; 何 錦涛; 小田 義崇; 谷川 聖; 王 磊; 津田 真寿美; 種井 善一; 田中 伸哉
  日本病理学会会誌, 112, 1, 383, 383, (一社)日本病理学会, 2023年03月
  日本語
• 進行性核上性麻痺にTDP43 pathologyを合併した一剖検例
  鍵谷 豪太; 種井 善一; 谷川 聖; 小田 義崇; 王 磊; 津田 真寿美; 大槻 美佳; 田中 伸哉
  日本病理学会会誌, 112, 1, 379, 379, (一社)日本病理学会, 2023年03月
  日本語
• 脳腫瘍に対する病理研究者としての克服戦略 ハイドロゲルによる髄膜腫幹細胞の探索(Strategies for overcoming the brain tumors presented by pathology researchers Search for meningioma stem cells using hydrogel)
  小田 義崇; 津田 真寿美; 湯澤 明夏; 王 磊; 鈴鹿 淳; ハビバ・ウンマ; 種井 善一; モーウリン・クリスチアン; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 112, 1, 184, 184, (一社)日本病理学会, 2023年03月
  英語
• TKIs耐性膠芽腫細胞の特性と耐性メカニズムの解析
  津田 真寿美; 王 磊; 小田 義崇; 谷川 聖; 種井 善一; 田中 伸哉
  日本病理学会会誌, 112, 1, 278, 278, (一社)日本病理学会, 2023年03月
  日本語
• ハイドロゲルを用いた中皮腫幹細胞の創出および治療標的分子の探索
  加藤 万里絵; 杉野 弘和; 津田 真寿美; 王 磊; 種井 善一; 小田 義崇; 谷川 聖; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 112, 1, 332, 332, (一社)日本病理学会, 2023年03月
  日本語
• 72歳女性のMultinodular and Vacuolating Neuronal Tumor of the cerebrumの1例
  寺島 祐樹; 種井 善一; 浅野目 卓; 黒田 花音; 小田 義崇; 谷川 聖; 王 磊; 津田 真寿美; 佐藤 憲市; 田中 伸哉
  日本病理学会会誌, 112, 1, 375, 375, (一社)日本病理学会, 2023年03月
  日本語
• 電子顕微鏡的検討を行ったラブドイド髄膜腫の一症例
  戸田 壮太郎; 種井 善一; 京野 里虹; 寺島 祐樹; 谷川 聖; 小田 義崇; 王 磊; 津田 真寿美; 瀬尾 善宣; 田中 伸哉
  日本病理学会会誌, 112, 1, 380, 380, (一社)日本病理学会, 2023年03月
  日本語
• 髄膜腫の骨化におけるEpithelial-mesenchymal transitionの関与についての検討
  京野 里虹; 種井 善一; 寺島 祐樹; 小田 義崇; 谷川 聖; 王 磊; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 112, 1, 381, 381, (一社)日本病理学会, 2023年03月
  日本語
• FFPE検体の質量分析による肺小細胞癌の脳転移関連分子の解析
  江端 美織; 何 錦涛; 小田 義崇; 谷川 聖; 王 磊; 津田 真寿美; 種井 善一; 田中 伸哉
  日本病理学会会誌, 112, 1, 383, 383, (一社)日本病理学会, 2023年03月
  日本語
• 進行性核上性麻痺にTDP43 pathologyを合併した一剖検例
  鍵谷 豪太; 種井 善一; 谷川 聖; 小田 義崇; 王 磊; 津田 真寿美; 大槻 美佳; 田中 伸哉
  日本病理学会会誌, 112, 1, 379, 379, (一社)日本病理学会, 2023年03月
  日本語
• Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer: An in vivo validation study.
  Tianyue Zhai; Takashi Mitamura; Lei Wang; Shimpei I Kubota; Masaaki Murakami; Shinya Tanaka; Hidemichi Watari
  Cancer medicine, 12, 8, 9697, 9708, 2023年02月22日, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Anti-angiogenic therapy with bevacizumab (BEV), an anti-VEGF antibody, plays a critical role in the treatment of ovarian cancer. However, despite an encouraging initial response, most tumors become resistant to BEV over time, and a new strategy that enables sustainable treatment using BEV is therefore needed. METHODS: To overcome the resistance to BEV in patients with ovarian cancer, we performed a validation study of combination therapy with BEV (10 mg/kg) and the CCR2 inhibitor BMS CCR2 22 (20 mg/kg) (BEV/CCR2i) using 3 consecutive patient-derived xenografts (PDXs) of immunodeficient mice. RESULTS: BEV/CCR2i demonstrated a significant effect of growth suppression in the BEV-resistant serous PDX and BEV-sensitive serous PDX compared with BEV (30.4% after the second cycle and 15.5% after the first cycle, respectively), and treatment cessation did not attenuate this effect. Tissue clearing and immunohistochemistry with an anti-α-SMA antibody suggested that BEV/CCR2i suppressed angiogenesis from the host mice more than BEV. In addition, human CD31 immunohistochemistry revealed that BEV/CCR2i decreased microvessels originating from the patients to a significantly greater degree than BEV. Regarding the BEV-resistant clear cell PDX, the effect of BEV/CCR2i was unclear during the first five cycles, but the following two cycles of increased-dose BEV/CCR2i (CCR2i 40 mg/kg) significantly suppressed tumor growth compared with BEV (28.3%) by inhibiting the CCR2B-MAPK pathway. CONCLUSIONS: BEV/CCR2i showed a sustained anticancer immunity-independent effect in human ovarian cancer that was more significant in serous carcinoma than in clear cell carcinoma.
• SARS-CoV-2変異株を用いたハムスター肺炎モデルの病理組織学的解析
  小田 義崇; 津田 真寿美; 王 磊; 谷川 聖; 種井 善一; 佐藤 佳; 福原 崇介; 田中 伸哉
  日本病理学会会誌, 111, 2, 113, 113, (一社)日本病理学会, 2022年10月
  日本語
• がんの可塑性・不均一性 バイオマテリアルによるがん幹細胞を誘導する可塑性の制御の解析(Analysis of regulatory mechanism of plasticity towards cancer stemness by hydrogels as biomaterial)
  田中 伸哉; 鈴鹿 淳; 小田 義崇; 斎藤 祐介; 王 磊; 津田 真寿美
  日本癌学会総会記事, 81回, S6, 3, (一社)日本癌学会, 2022年09月
  英語
• ハイドロゲルを用いた髄膜腫がん幹細胞マーカーの検索(Identification of novel stemness marker of meningioma by using hydrogel)
  小田 義崇; 津田 真寿美; 湯澤 明夏; 王 磊; 谷川 聖; 種井 善一; グン 剣萍; 田中 伸哉
  日本癌学会総会記事, 81回, P, 2111, (一社)日本癌学会, 2022年09月
  英語
• Virological characteristics of the SARS-CoV-2 Omicron BA.2 subvariants including BA.4 and BA.5
  Izumi Kimura; Daichi Yamasoba; Tomokazu Tamura; Naganori Nao; Tateki Suzuki; Yoshitaka Oda; Shuya Mitoma; Jumpei Ito; Hesham Nasser; Jiri Zahradnik; Keiya Uriu; Shigeru Fujita; Yusuke Kosugi; Lei Wang; Masumi Tsuda; Mai Kishimoto; Hayato Ito; Rigel Suzuki; Ryo Shimizu; M.S.T. Monira Begum; Kumiko Yoshimatsu; Kanako Terakado Kimura; Jiei Sasaki; Kaori Sasaki-Tabata; Yuki Yamamoto; Tetsuharu Nagamoto; Jun Kanamune; Kouji Kobiyama; Hiroyuki Asakura; Mami Nagashima; Kenji Sadamasu; Kazuhisa Yoshimura; Kotaro Shirakawa; Akifumi Takaori-Kondo; Jin Kuramochi; Gideon Schreiber; Ken J. Ishii; Takao Hashiguchi; Terumasa Ikeda; Akatsuki Saito; Takasuke Fukuhara; Shinya Tanaka; Keita Matsuno; Kei Sato
  Cell, 185, 21, 3992, 4007, Elsevier BV, 2022年09月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, After the global spread of the SARS-CoV-2 Omicron BA.2, some BA.2 subvariants, including BA.2.9.1, BA.2.11, BA.2.12.1, BA.4, and BA.5, emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these BA.2 subvariants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1/2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. We further provided the structure of the BA.4/5 spike receptor-binding domain that binds to human ACE2 and considered how the substitutions in the BA.4/5 spike play roles in ACE2 binding and immune evasion. Moreover, experiments using hamsters suggested that BA.4/5 is more pathogenic than BA.2. Our multiscale investigations suggest that the risk of BA.2 subvariants, particularly BA.4/5, to global health is greater than that of original BA.2.
• Hydroxyapatite-hybridized double-network hydrogel surface enhances differentiation of bone marrow-derived mesenchymal stem cells to osteogenic cells.
  Takuma Kaibara; Lei Wang; Masumi Tsuda; Takayuki Nonoyama; Takayuki Kurokawa; Norimasa Iwasaki; Jian Ping Gong; Shinya Tanaka; Kazunori Yasuda
  Journal of biomedical materials research. Part A, 110, 4, 747, 760, 2022年04月, ［国際誌］
  英語, 研究論文（学術雑誌）, Recently, we have developed a hydroxyapatite (HAp)-hybridized double-network (DN) hydrogel (HAp/DN gel), which can robustly bond to the bone tissue in the living body. The purpose of this study is to clarify whether the HAp/DN gel surface can differentiate the bone marrow-derived mesenchymal stem cells (MSCs) to osteogenic cells. We used the MSCs which were harvested from the rabbit bone marrow and cultured on the polystyrene (PS) dish using the autogenous serum-supplemented medium. First, we confirmed the properties of MSCs by evaluating colony forming unit capacity, expression of MSC markers using flow cytometry, and multidifferential capacity. Secondly, polymerase chain reaction analysis demonstrated that the HAp/DN gel surface significantly enhanced mRNA expression of the eight osteogenic markers (TGF-β1, BMP-2, Runx2, Col-1, ALP, OPN, BSP, and OCN) in the cultured MSCs at 7 days than the PS surfaces (p < 0.0001), while the DN gel and HAp surfaces provided no or only a slight effect on the expression of these markers except for Runx2. Additionally, the alkaline phosphatase activity was significantly higher in the cells cultured on the HAp/DN gel surface than in the other three material surfaces (p < 0.0001). Thirdly, when the HAp/DN gel plug was implanted into the rabbit bone marrow, MSC marker-positive cells were recruited in the tissue generated around the plug at 3 days, and Runx2 and OCN were highly expressed in these cells. In conclusion, this study demonstrated that the HAp/DN gel surface can differentiate the MSCs into osteogenic cells.
• 細胞外基質の電位変化に伴うJCウイルス増殖の制御
  谷川 聖; 野々山 貴行; 津田 真寿美; 王 磊; 種井 善一; Gong Jian Ping; 田中 伸哉
  日本病理学会会誌, 111, 1, 263, 263, (一社)日本病理学会, 2022年03月
  日本語
• 細胞外基質の電位変化に伴うJCウイルス増殖の制御
  谷川 聖; 野々山 貴行; 津田 真寿美; 王 磊; 種井 善一; Gong Jian Ping; 田中 伸哉
  日本病理学会会誌, 111, 1, 263, 263, (一社)日本病理学会, 2022年03月
  日本語
• Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant.
  Rigel Suzuki; Daichi Yamasoba; Izumi Kimura; Lei Wang; Mai Kishimoto; Jumpei Ito; Yuhei Morioka; Naganori Nao; Hesham Nasser; Keiya Uriu; Yusuke Kosugi; Masumi Tsuda; Yasuko Orba; Michihito Sasaki; Ryo Shimizu; Ryoko Kawabata; Kumiko Yoshimatsu; Hiroyuki Asakura; Mami Nagashima; Kenji Sadamasu; Kazuhisa Yoshimura; Hirofumi Sawa; Terumasa Ikeda; Takashi Irie; Keita Matsuno; Shinya Tanaka; Takasuke Fukuhara; Kei Sato
  Nature, 603, 7902, 700, 705, 2022年03月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, The emergence of the Omicron variant of SARS-CoV-2 is an urgent global health concern1. In this study, our statistical modelling suggests that Omicron has spread more rapidly than the Delta variant in several countries including South Africa. Cell culture experiments showed Omicron to be less fusogenic than Delta and than an ancestral strain of SARS-CoV-2. Although the spike (S) protein of Delta is efficiently cleaved into two subunits, which facilitates cell-cell fusion2,3, the Omicron S protein was less efficiently cleaved compared to the S proteins of Delta and ancestral SARS-CoV-2. Furthermore, in a hamster model, Omicron showed decreased lung infectivity and was less pathogenic compared to Delta and ancestral SARS-CoV-2. Our multiscale investigations reveal the virological characteristics of Omicron, including rapid growth in the human population, lower fusogenicity and attenuated pathogenicity.
• Novel rapid immunohistochemistry using an alternating current electric field identifies Rac and Cdc42 activation in human colon cancer FFPE tissues.
  Masumi Tsuda; Runa Horio; Lei Wang; Tomoko Takenami; Jun Moriya; Jun Suzuka; Hirokazu Sugino; Zenichi Tanei; Mishie Tanino; Shinya Tanaka
  Scientific reports, 12, 1, 1733, 1733, 2022年02月02日, ［国際誌］
  英語, 研究論文（学術雑誌）, It is important to determine the activation status of Rac and Cdc42 in cancer tissues for the prediction of metastasis and patient prognosis. However, it has been impossible to detect their spatial activation on formalin-fixed paraffin embedded (FFPE) surgical specimens thus far. Here, we established a novel detection technique for activated Rac/Cdc42 in human colon cancer FFPE tissues by using a p21-activated kinase (PAK)-Rac binding domain (RBD) detection probe fused with glutathione S-transferase (GST), designated GST-PAK-RBD, and novel rapid-immunohistochemistry (R-IHC) systems using noncontact alterating-current electric field mixing, although there is a technical limitation in that it may not distinguish between Rac members and Cdc42. In 50 cases of colon cancer, various activation patterns of Rac/Cdc42 were observed, which were designated plasma membrane, cytoplasm, mixed pattern, and polarized distribution. The activity was striking in the invasive fronts of tumors and significantly correlated with tumor invasion properties evaluated by TNM classification. Of note, in tissue microarray (TMA) samples, 29 of 33 cases demonstrated higher Rac1/Cdc42 activity in the tumor area than the corresponding normal mucosa. In addition, positive correlations were detected between Rac/Cdc42 activity and clinicopathological factors such as venous and lymphatic vessel invasion. These results suggest that understanding Rac and Cdc42 activations in cancer tissues would be valuable as an option for molecular therapy as personalized medicine.
• Germline PRDM1 Variant rs2185379 in Long-Term Recurrence-Free Survivors of Advanced Ovarian Cancer.
  Takashi Mitamura; Tianyue Zhai; Kanako C Hatanaka; Yutaka Hatanaka; Toraji Amano; Lei Wang; Shinya Tanaka; Hidemichi Watari
  Pharmacogenomics and personalized medicine, 15, 977, 984, 2022年, ［国際誌］
  英語, 研究論文（学術雑誌）, PURPOSE: To identify the germline genetic characteristics of long-term recurrence-free survivors that can be applied to establishing a new strategy for curing advanced cancer, we investigated the whole-genome single nucleotide variants of ovarian cancer patients. PATIENTS AND METHODS: DNA specimens were obtained from rare long-term recurrence-free survivors with FIGO stage III-IV ovarian cancer with no recurrence for 8-23 years after primary treatments for a whole-genome analysis of approximately 660,000 single nucleotide variants. We then established a mouse model with a notable gene alteration by CRISPR/Cas9 to confirm the biological role. RESULTS: The long-term recurrence-free survivors more frequently had germline heterozygous variant rs2185379 of the PRDM1 gene exon than patients with early recurrence (6.8-fold, P=0.013) and the general population. In the mouse model, primary intraperitoneal disseminated tumors of allograft ID8 were significantly smaller in the germline heterozygous rs2185379 group than in the wild-type group (57.4% decrease, P=0.008). Immunohistochemistry showed that the area of distribution of infiltrating T lymphocytes with positive CD8 staining was significantly increased in the germline heterozygous rs2185379 group in comparison to the wild-type group. CONCLUSION: Germline heterozygous rs2185379 in PRDM1 is correlated with an excellent prognosis and can be used to establish a new strategy for treating advanced ovarian cancer.
• Aberrant expression of MYD88 via RNA-controlling CNOT4 and EXOSC3 in colonic mucosa impacts generation of colonic cancer.
  Masumi Tsuda; Misa Noguchi; Tsuyoshi Kurai; Yuji Ichihashi; Koki Ise; Lei Wang; Yusuke Ishida; Mishie Tanino; Satoshi Hirano; Masahiro Asaka; Shinya Tanaka
  Cancer science, 112, 12, 5100, 5113, 2021年12月, ［国際誌］
  英語, 研究論文（学術雑誌）, In 2020, the worldwide incidence and mortality of colorectal cancer (CRC) were third and second, respectively. As the 5-y survival rate is low when CRC is diagnosed at an advanced stage, a reliable method to predict CRC susceptibility is important for preventing the onset and development and improving the prognosis of CRC. Therefore, we focused on the normal colonic mucosa to investigate changes in gene expression that may induce subsequent genetic alterations that induce malignant transformation. Comprehensive gene expression profiling in the normal mucosa adjacent to colon cancer (CC) compared with tissue from non-colon cancer patients was performed. PCR arrays and qRT-PCR revealed that the expression of 5 genes involved in the immune response, including MYD88, was increased in the normal mucosa of CC patients. The expression levels of MYD88 were strikingly increased in precancerous normal mucosa specimens, which harbored no somatic mutations, as shown by immunohistochemistry. Microarray analysis identified 2 novel RNA-controlling molecules, EXOSC3 and CNOT4, that were significantly upregulated in the normal mucosa of CC patients and were clearly visualized in the nuclei. Forced expression of EXOSC3 and CNOT4 in human colonic epithelial cells increased the expression of IFNGR1, MYD88, NFκBIA, and STAT3 and activated ERK1/2 and JNK in 293T cells. Taken together, these results suggested that, in the inflamed mucosa, EXOSC3- and CNOT4-mediated RNA stabilization, including that of MYD88, may trigger the development of cancer and can serve as a potential predictive marker and innovative treatment to control cancer development.
• Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation.
  Akatsuki Saito; Takashi Irie; Rigel Suzuki; Tadashi Maemura; Hesham Nasser; Keiya Uriu; Yusuke Kosugi; Kotaro Shirakawa; Kenji Sadamasu; Izumi Kimura; Jumpei Ito; Jiaqi Wu; Kiyoko Iwatsuki-Horimoto; Mutsumi Ito; Seiya Yamayoshi; Samantha Loeber; Masumi Tsuda; Lei Wang; Seiya Ozono; Erika P Butlertanaka; Yuri L Tanaka; Ryo Shimizu; Kenta Shimizu; Kumiko Yoshimatsu; Ryoko Kawabata; Takemasa Sakaguchi; Kenzo Tokunaga; Isao Yoshida; Hiroyuki Asakura; Mami Nagashima; Yasuhiro Kazuma; Ryosuke Nomura; Yoshihito Horisawa; Kazuhisa Yoshimura; Akifumi Takaori-Kondo; Masaki Imai; Shinya Tanaka; So Nakagawa; Terumasa Ikeda; Takasuke Fukuhara; Yoshihiro Kawaoka; Kei Sato
  Nature, 602, 7896, 300, 306, 2021年11月25日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, During the current SARS-CoV-2 pandemic, a variety of mutations have accumulated in the viral genome, and currently, four variants of concern (VOCs) are considered potentially hazardous to human society1. The recently emerged B.1.617.2/Delta VOC is closely associated with the COVID-19 surge that occurred in India in the spring of 20212. However, its virological properties remain unclear. Here, we show that the B.1.617.2/Delta variant is highly fusogenic and notably more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates spike protein cleavage and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity than its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity.
• ハイドロゲルを用いた新規髄膜腫治療標的分子の検討(Analysis of novel therapeutic target for meningioma using hydrogel)
  小田 義崇; 津田 真寿美; 湯澤 明夏; 王 磊; Umma Habiba; 杉野 弘和; 種井 善一; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 110, 2, 110, 110, (一社)日本病理学会, 2021年10月
  英語
• ハイドロゲルを用いた新規髄膜腫治療標的分子の検討(Analysis of novel therapeutic target for meningioma using hydrogel)
  小田 義崇; 津田 真寿美; 湯澤 明夏; 王 磊; Umma Habiba; 杉野 弘和; 種井 善一; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 110, 2, 110, 110, (一社)日本病理学会, 2021年10月
  英語
• Fast in vivo fixation of double network hydrogel to bone by monetite surface hybridization
  Takayuki Nonoyama; Lei Wang; Ryuji Kiyama; Naohiro Kashimura; Kazunori Yasuda; Shinya Tanaka; Takayuki Kurokawa; Jian Ping Gong
  JOURNAL OF THE CERAMIC SOCIETY OF JAPAN, 129, 9, 584, 589, 2021年09月
  英語, 研究論文（学術雑誌）
• Rapid reprogramming of tumour cells into cancer stem cells on double-network hydrogels
  Jun Suzuka; Masumi Tsuda; Lei Wang; Shinji Kohsaka; Karin Kishida; Shingo Semba; Hirokazu Sugino; Sachiyo Aburatani; Martin Frauenlob; Takayuki Kurokawa; Shinya Kojima; Toshihide Ueno; Yoshihiro Ohmiya; Hiroyuki Mano; Kazunori Yasuda; Jian Ping Gong; Shinya Tanaka
  Nature Biomedical Engineering, 5, 8, 914, 925, Springer Science and Business Media LLC, 2021年03月29日
  研究論文（学術雑誌）
• ハイドロゲルによる癌幹細胞性の誘導を利用した髄膜腫の新規治療標的分子の検索
  小田 義崇; 津田 真寿美; 湯澤 明夏; 王 磊; 杉野 弘和; 鈴鹿 淳; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 110, 1, 225, 225, (一社)日本病理学会, 2021年03月
  日本語
• Involvement of BMP and Wnt Signals Leadingto Epithelial-Mesenchymal Transition in Colon Adenocarcinoma with Heterotopic Ossification.
  Naho Katono; Masumi Tsuda; Jun Suzuka; Yoshitaka Oda; Lei Wang; Zen-Ichi Tanei; Mishie Tanino; Takanobu Ohata; Eisuke Nagabuchi; Yusuke Ishida; Shunsuke Kimura; Toshihiko Iwanaga; Shinya Tanaka
  Annals of clinical and laboratory science, 51, 2, 271, 276, 2021年03月, ［国際誌］
  英語, 研究論文（学術雑誌）, Here we present the case of a 73-year-old male with rectal adenocarcinoma with heterotopic ossification (HO). Cancer-associated HO in the digestive system is rare. Thus, the precise mechanism and clinicopathological significance of HO have not yet been defined. To clarify the molecular mechanisms of HO, we analyzed the expression levels of signaling molecules related to epithelial-mesenchymal transition (EMT) that lead to ossification in the tumor cells discriminating the ossified area (HO-area) and non-ossified area (non-HO area). Expression levels of BMP4 were elevated in both areas, whereas BMP2 was specifically increased in the HO-area by qPCR. EMT-related molecules such as Snail and Slug were especially higher in the HO-area. By immunohistochemistry, the expression of Smad4, nuclear staining of β-catenin, and the phosphorylated form of GSK-3β were detectable in both areas, and GSK-3β was highly phosphorylated in the HO-area. The tumor growth rate was extremely high, with the Ki-67 labeling index at 90%. In the HO-area, osteoblasts with alkaline phosphatase expression were distributed surrounding the tumor cells. This is the first demonstration of the involvement of EMT in HO of colon cancer through BMP/SMAD and WNT/β-catenin signaling pathways, which are especially prominent in the HO-area leading to the osteogenic property.
• Isotope Microscopic Observation of Osteogenesis Process Forming Robust Bonding of Double Network Hydrogel to Bone.
  Takayuki Nonoyama; Lei Wang; Masumi Tsuda; Yuki Suzuki; Ryuji Kiyama; Kazunori Yasuda; Shinya Tanaka; Kousuke Nagata; Ryosuke Fujita; Naoya Sakamoto; Noriyuki Kawasaki; Hisayoshi Yurimoto; Jian Ping Gong
  Advanced healthcare materials, 10, 3, e2001731, 2021年02月, ［国際誌］
  英語, 研究論文（学術雑誌）, Tough double network (DN) hydrogels are promising substitutes of soft supporting tissues such as cartilage and ligaments. For such applications, it is indispensable to robustly fix the hydrogels to bones with medically feasible methods. Recently, robustly bonding the DN hydrogels to defected bones of rabbits in vivo has been proved successful. The low crystalline hydroxyapatite (HAp) of calcium-phosphate-hydroxide salt coated on the surface layer of the DN hydrogels induced spontaneous osteogenesis penetrating into the semi-permeable hydrogels to form a gel/bone composite layer. In this work, the 44 Ca isotope-doped HAp/DN hydrogel is implanted in a defect of rabbit femoral bone and the dynamic osteogenesis process at the gel/bone interface is analyzed by tracing the calcium isotope ratio using isotope microscopy. The synthetic HAp hybridized on the surface layer of DN gel dissolves rapidly in the first two weeks by inflammation, and then the immature bone with a gradient structure starts to form in the gel region, reutilizing the dissolved Ca ions. These results reveal, for the first time, that synthetic HAp is reutilized for osteogenesis. These facts help to understand the lifetime of bone absorbable materials and to elucidate the mechanism of spontaneous, non-toxic, but strong fixation of hydrogels to bones.
• CMKLR1は肝癌幹細胞標的治療のための候補分子である
  谷 道夫; 津田 真寿美; 鈴鹿 淳; 王 磊; 武冨 紹信; 田中 伸哉
  日本癌学会総会記事, 79回, PJ14, 1, (一社)日本癌学会, 2020年10月
  英語
• CMKLR1は肝癌幹細胞標的治療のための候補分子である
  谷 道夫; 津田 真寿美; 鈴鹿 淳; 王 磊; 武冨 紹信; 田中 伸哉
  日本癌学会総会記事, 79回, PJ14, 1, (一社)日本癌学会, 2020年10月
  英語
• Chitin-Based Double-Network Hydrogel as Potential Superficial Soft-Tissue-Repairing Materials
  Junchao Huang; Martin Frauenlob; Yuki Shibata; Lei Wang; Tasuku Nakajima; Takayuki Nonoyama; Masumi Tsuda; Shinya Tanaka; Takayuki Kurokawa; Jian Ping Gong
  Biomacromolecules, American Chemical Society (ACS), 2020年09月27日
  研究論文（学術雑誌）
• バイオマテリアルによる肝癌幹細胞の新規誘導法の開発とその解析
  谷 道夫; 津田 真寿美; 鈴鹿 淳; 王 磊; 杉野 弘和; 谷川 聖; 石田 雄介; グン 剣萍; 田中 伸哉; 武冨 紹信
  日本外科学会定期学術集会抄録集, 120回, DP, 6, (一社)日本外科学会, 2020年08月
  日本語
• バイオマテリアルによる肝癌幹細胞の新規誘導法の開発とその解析
  谷 道夫; 津田 真寿美; 鈴鹿 淳; 王 磊; 杉野 弘和; 谷川 聖; 石田 雄介; グン 剣萍; 田中 伸哉; 武冨 紹信
  日本外科学会定期学術集会抄録集, 120回, DP, 6, (一社)日本外科学会, 2020年08月
  日本語
• Signaling adaptor protein Crk is involved in malignant feature of pancreatic cancer associated with phosphorylation of c-Met.
  Satoko Uemura; Lei Wang; Masumi Tsuda; Jun Suzuka; Satoshi Tanikawa; Hirokazu Sugino; Toru Nakamura; Tomoko Mitsuhashi; Satoshi Hirano; Shinya Tanaka
  Biochemical and biophysical research communications, 524, 2, 378, 384, 2020年04月02日, ［国際誌］
  英語, 研究論文（学術雑誌）, Signaling adaptor protein Crk has been shown to play an important role in various human cancers. Crk links tyrosine kinases and guanine nucleotide exchange factors (GEFs) such as C3G and Dock180 to activate small G-proteins Rap and Rac, respectively. In pancreatic cancer, various molecular targeted therapies have provided no significant therapeutic benefit for the patients so far due to constitutive activation of KRAS by frequent KRAS mutation. Therefore, the establishment of novel molecular targeted therapy in KRAS-independent manner is required. Here, we investigated a potential of Crk as a therapeutic target in pancreatic cancer. Immunohistochemistry on human pancreatic cancer specimens revealed that the patients with high expression of Crk had a worse prognosis than those with low expression. We established Crk-knockdown pancreatic cancer cells by siRNA using PANC-1, AsPC-1, and MIA PaCa-2 cells, which showed decreased cell proliferation, invasion, and adhesion. In Crk-knockdown pancreatic cancer cells, the decrease of c-Met phosphorylation was observed. In the orthotopic xenograft model, Crk depletion prolonged survival of mice significantly. Thus, signaling adaptor protein Crk is involved in malignant potential of pancreatic cancer associated with decrease of c-Met phosphorylation, and Crk can be considered to be a potential therapeutic molecular target.
• ハイドロゲルを用いた髄膜腫治療標的分子の検索
  小田 義崇; 津田 真寿美; 湯澤 明夏; 王 磊; 杉野 弘和; 鈴鹿 淳; 廣田 聡; 今城 正道; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 109, 1, 319, 319, (一社)日本病理学会, 2020年03月
  日本語
• Emery-Dreifuss型筋ジストロフィーに伴う心不全の1剖検例
  五味川 龍; 石田 雄介; 桑原 健; 石垣 隆弘; 谷川 聖; 小田 義崇; 王 磊; 杉野 弘和; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 109, 1, 492, 492, (一社)日本病理学会, 2020年03月
  日本語
• 前立腺癌のGleason pattern評価のためのSemantic segmentationモデル及びRaspberry Pi端末を用いた応用
  遠田 建; 伊勢 昂生; 石田 雄介; 桑原 健; 谷川 聖; 小田 義崇; 王 磊; 杉野 弘和; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 109, 1, 496, 496, (一社)日本病理学会, 2020年03月
  日本語
• 新規変異BRAFV601K変異を認める良性脳腫瘍(毛様体性星細胞腫)の一例
  榎枝 未紗; 小田 義崇; 津田 真寿美; 飛弾 一利; 杉野 弘和; 谷川 聖; 鈴鹿 淳; 王 磊; 石田 雄介; 田中 伸哉
  日本病理学会会誌, 109, 1, 497, 497, (一社)日本病理学会, 2020年03月
  日本語
• Emery-Dreifuss型筋ジストロフィーに伴う心不全の1剖検例
  五味川 龍; 石田 雄介; 桑原 健; 石垣 隆弘; 谷川 聖; 小田 義崇; 王 磊; 杉野 弘和; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 109, 1, 492, 492, (一社)日本病理学会, 2020年03月
  日本語
• 前立腺癌のGleason pattern評価のためのSemantic segmentationモデル及びRaspberry Pi端末を用いた応用
  遠田 建; 伊勢 昂生; 石田 雄介; 桑原 健; 谷川 聖; 小田 義崇; 王 磊; 杉野 弘和; 津田 真寿美; 田中 伸哉
  日本病理学会会誌, 109, 1, 496, 496, (一社)日本病理学会, 2020年03月
  日本語
• 新規変異BRAFV601K変異を認める良性脳腫瘍(毛様体性星細胞腫)の一例
  榎枝 未紗; 小田 義崇; 津田 真寿美; 飛弾 一利; 杉野 弘和; 谷川 聖; 鈴鹿 淳; 王 磊; 石田 雄介; 田中 伸哉
  日本病理学会会誌, 109, 1, 497, 497, (一社)日本病理学会, 2020年03月
  日本語
• Autopsy findings in the early stage of amyotrophic lateral sclerosis with "dropped head" syndrome.
  Tanikawa S; Tanino M; Wang L; Ishikawa M; Miyazaki M; Tsuda M; Orba Y; Sawa H; Matoba K; Nakamura N; Nagashima K; Hall WW; Tanaka S
  Neuropathology : official journal of the Japanese Society of Neuropathology, 39, 5, 374, 377, Wiley, 2019年10月, ［査読有り］
  研究論文（学術雑誌）
• 血管新生阻害薬の有効利用
  三田村 卓; 王 磊; 翟 天玥; 渡利 英道
  BIO Clinica, 34, 10, 1020, 1022, (株)北隆館, 2019年09月, ［査読有り］, ［招待有り］
  日本語
• Exosomes containing ErbB2/CRK induce vascular growth in premetastatic niches and promote metastasis of bladder cancer.
  Yoshida K; Tsuda M; Matsumoto R; Semba S; Wang L; Sugino H; Tanino M; Kondo T; Tanabe K; Tanaka S
  Cancer science, 110, 7, 2119, 2132, 2019年07月, ［査読有り］, ［国際誌］
  英語, Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin-based combination chemotherapy have been developed. Therefore, it is an urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM-UC-3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM-UC-3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM-UC-3-derived exosomes in a CRK-dependent manner; the exosomes significantly increased proliferation and invasion properties of low-grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM-UC-3-derived exosomes, i.v. implanted UM-UC-3 cells were trapped with surrounding PKH67-labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK-depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.
• miR-23a-HOXD10経路はglial-mesenchymal transitionを介して膠芽腫浸潤能を亢進する
  津田 真寿美; 谷地 一博; 高阪 真路; 王 磊; 小田 義崇; 谷川 聖; 大場 雄介; 田中 伸哉
  日本病理学会会誌, 108, 1, 311, 312, (一社)日本病理学会, 2019年04月
  日本語
• バイオマテリアルによる肝癌幹細胞の新規誘導法
  谷 道夫; 津田 真寿美; 鈴鹿 淳; 王 磊; 杉野 弘和; 谷川 聖; 石田 雄介; グン 剣萍; 田中 伸哉; 武冨 紹信
  日本外科学会定期学術集会抄録集, 119回, PS, 6, (一社)日本外科学会, 2019年04月
  日本語
• 初回治療から18年後に生じた多臓器進展を伴うホジキンリンパ腫の一剖検例
  五味川 龍; 杉野 弘和; 白鳥 聡一; 石田 雄介; 王 磊; 畑中 佳奈子; 松野 吉宏; 豊嶋 崇徳; 田中 伸哉
  日本病理学会会誌, 108, 1, 453, 453, (一社)日本病理学会, 2019年04月
  日本語
• Tough and Self-Recoverable Thin Hydrogel Membranes for Biological Applications
  Ya Nan Ye; Martin Frauenlob; Lei Wang; Masumi Tsuda; Tao Lin Sun; Kunpeng Cui; Riku Takahashi; Huijie Zhang; Tasuku Nakajima; Takayuki Nonoyama; Takayuki Kurokawa; Shinya Tanaka; Jian Ping Gong
  Advanced Functional Materials, 28, 31, 1801489, 2018年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• 新規技術を用いた新しい研究アプローチ 高分子ハイドロゲルによる癌幹細胞へのリプログラミング誘導技術
  津田 真寿美; 鈴鹿 淳; 王 磊; 仙葉 慎吾; 油谷 幸代; 黒川 孝幸; 近江谷 克裕; 安田 和則; グン 剣萍; 田中 伸哉
  日本病理学会会誌, 107, 1, 217, 217, (一社)日本病理学会, 2018年04月
  日本語
• 神経再生工学における両電荷を有するハイドロゲルの開発
  谷川 聖; 仙葉 慎吾; 津田 真寿美; 王 磊; 谷野 美智枝; 石田 雄介; 杉野 弘和; 鈴鹿 淳; 田中 伸哉
  日本病理学会会誌, 107, 1, 329, 329, (一社)日本病理学会, 2018年04月
  日本語
• 悪性神経膠腫におけるIDH1遺伝子変異による放射線照射後変化の解析(Analysis of the effect of IDH1 mutation on the radiosensitivity in malignant glioma)
  北崎 アリサ; 谷野 美智枝; 九笹 めい; 杉野 弘和; 王 磊; 石田 雄介; 津田 真寿美; 五十嵐 香織; 曽我 朋義; 田中 伸哉
  日本病理学会会誌, 107, 1, 379, 379, (一社)日本病理学会, 2018年04月
  英語
• 悪性中皮腫におけるOTUB1の役割
  九笹 めい; 谷野 美智枝; 北崎 アリサ; 杉野 弘和; 石田 雄介; 王 磊; 津田 真寿美; 高澤 啓; 平野 博嗣; 田中 伸哉
  日本病理学会会誌, 107, 1, 406, 406, (一社)日本病理学会, 2018年04月
  日本語
• 末梢性T細胞リンパ腫の剖検時に見出された硬化性胸腺腫の一例
  飯田 圭祐; 植田 沙也加; 杉野 弘和; 曾澤 佳昭; 谷野 美智枝; 石田 雄介; 王 磊; 田中 伸哉
  日本病理学会会誌, 107, 1, 533, 533, (一社)日本病理学会, 2018年04月
  日本語
• Tough and Self‐Recoverable Thin Hydrogel Membranes for Biological Applications
  Ye YN; Frauenlob M; Wang L; Tsuda M; Sun TL; Cui K; Takahashi R; Ahang HJ; Nakajima T; Nonoyama T; Kurokawa T; Tanaka S; Gong JP
  Advanced Functional Materials, 29, 1801489, 1, 11, 2018年03月, ［査読有り］
• Chorionic Gonadotropin-β Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis
  Kawamata F; Nishihara H; Homma S; Kato Y; Tsuda M; Konishi Y; Wang L; Kohsaka S; Liu C; Yoshida T; Tanino M; Tanaka S; Kawamura H; Kamiyama T; Taketomi A
  Am J Pathol., 188, 1, 204, 215, 2018年01月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, Ectopic production of free β human chorionic gonadotropin (hCGβ) has been associated with aggressive behavior in non-trophoblastic tumors. hCGβ shares common evolutionary sequences with transforming growth factor-β (TGF-β), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGβ during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGβ-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGβ positivity [13/80 (16.3%)] was lower than serologic hCGβ positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGβ-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGβ altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGβ-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-β receptor inhibitors (P < 0.05). hCGβ thus induces EMT via the TGF-β signaling pathway, and it may represent a molecular target in CRC treatment.
• A clinicopathological analysis of six autopsy cases of sudden unexpected death due to infectious aortitis in patients with aortic tears
  Marin Ishikawa; Mishie Ann Tanino; Masaya Miyazaki; Taichi Kimura; Yusuke Ishida; Lei Wang; Masumi Tsuda; Hiroshi Nishihara; Kazuo Nagashima; Shinya Tanaka
  Internal Medicine, 57, 10, 1375, 1380, Japanese Society of Internal Medicine, 2018年, ［査読有り］
  英語, 研究論文（学術雑誌）
• Loss of TRIM29 promotes cell invasion in squamous cell carcinoma via alterations in keratin distribution.
  Teruki Yanagi; Masashi Watanabe; Hiroo Hata; Shinya Kitamura; Keisuke Imafuku; Hiroko Yanagi; Akihiro Homma; Lei Wang; Hidehisa Takahashi; Hiroshi Shimizu; Shigetsugu Hatakeyama
  Cancer Research, 78, 24, 6795, 6806, 2018年, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, : TRIM29 (tripartite motif-containing protein 29) is a TRIM family protein that has been implicated in breast, colorectal, and pancreatic cancers. However, its role in stratified squamous epithelial cells and tumors has not been elucidated. Here, we investigate the expression of TRIM29 in cutaneous head and neck squamous cell carcinomas (SCC) and its functions in the tumorigenesis of such cancers. TRIM29 expression was lower in malignant SCC lesions than in adjacent normal epithelial tissue or benign tumors. Lower expression of TRIM29 was associated with higher SCC invasiveness. Primary tumors of cutaneous SCC showed aberrant hypermethylation of TRIM29. Depletion of TRIM29 increased cancer cell migration and invasion; conversely, overexpression of TRIM29 suppressed these. Comprehensive proteomics and immunoprecipitation analyses identified keratins and keratin-interacting protein FAM83H as TRIM29 interactors. Knockdown of TRIM29 led to ectopic keratin localization of keratinocytes. In primary tumors, lower TRIM29 expression correlated with the altered expression of keratins. Our findings reveal an unexpected role for TRIM29 in regulating the distribution of keratins, as well as in the migration and invasion of SCC. They also suggest that the TRIM29-keratin axis could serve as a diagnostic and prognostic marker in stratified epithelial tumors and may provide a target for SCC therapeutics. SIGNIFICANCE: These findings identify TRIM29 as a novel diagnostic and prognostic marker in stratified epithelial tissues.
• miR-23a promotes invasion of glioblastoma via HOXD10-regulated glial-mesenchymal transition.
  Kazuhiro Yachi; Masumi Tsuda; Shinji Kohsaka; Lei Wang; Yoshitaka Oda; Satoshi Tanikawa; Yusuke Ohba; Shinya Tanaka
  Signal transduction and targeted therapy, 3, 33, 33, 2018年, ［査読有り］, ［国際誌］
  英語, Glioblastoma is the most aggressive and invasive brain tumor and has a poor prognosis; elucidating the underlying molecular mechanisms is essential to select molecular targeted therapies. Here, we investigated the effect of microRNAs on the marked invasiveness of glioblastoma. U373 glioblastoma cells were infected with 140 different microRNAs from an OncomiR library, and the effects of the invasion-related microRNAs and targeted molecules were investigated after repeated Matrigel invasion assays. Screening of the OncomiR library identified miR-23a as a key regulator of glioblastoma invasion. In six glioblastoma cell lines, a positive correlation was detected between the expression levels of miR-23a and invasiveness. A luciferase reporter assay demonstrated that homeobox D10 (HOXD10) was a miR-23a-target molecule, which was verified by high scores from both the PicTar and miRanda algorithms. Forced expression of miR-23a induced expression of invasion-related molecules, including uPAR, RhoA, and RhoC, and altered expression of glial-mesenchymal transition markers such as Snail, Slug, MMP2, MMP9, MMP14, and E-cadherin; however, these changes in expression levels were reversed by HOXD10 overexpression. Thus, miR-23a significantly promoted invasion of glioblastoma cells with polarized formation of focal adhesions, while exogenous HOXD10 overexpression reversed these phenomena. Here, we identify miR-23a-regulated HOXD10 as a pivotal regulator of invasion in glioblastoma, providing a novel mechanism for the aggressive invasiveness of this tumor and providing insight into potential therapeutic targets.
• The Anti-tumor Effect of Cabozantinib on Ovarian Clear Cell Carcinoma In Vitro and In Vivo
  Makiko Nakatani; Hidemichi Watari; Takashi Mitamura; Lei Wang; Yutaka Hatanaka; Kanako C. Hatanaka; Kohei Honda; Toshiyuki Nomura; Hiroshi Nishihara; Shinya Tanaka; Noriaki Sakuragi
  ANTICANCER RESEARCH, 37, 11, 6125, 6132, 2017年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• 悪性中皮腫におけるOTUB1の発現
  九笹 めい; 谷野 美智枝; 北崎 アリサ; 杉野 弘和; 石田 雄介; 王 磊; 津田 真寿美; 高澤 啓; 平野 博嗣; 田中 伸哉
  日本癌学会総会記事, 76回, P, 3277, 日本癌学会, 2017年09月
  英語
• 多形黄色星細胞腫におけるBRAF遺伝子変異(BRAF V600E)とp16の発現の検討
  谷野 美智枝; 南條 博; 津田 真寿美; 杉野 弘和; 王 磊; 石田 雄介; 田中 伸哉
  日本癌学会総会記事, 76回, P, 3317, 日本癌学会, 2017年09月
  英語
• 悪性神経膠腫においてIDH1遺伝子変異は放射線照射後のアポトーシスを亢進する
  北崎 アリサ; 谷野 美智枝; 九笹 めい; 杉野 弘和; 王 磊; 石田 雄介; 仙葉 慎吾; 津田 真寿美; 五十嵐 香織; 曽我 朋義; 田中 伸哉
  日本癌学会総会記事, 76回, P, 3323, 日本癌学会, 2017年09月
  英語
• Notch 1 regulates invasion and metastasis of head and neck squamous cell carcinoma by inducing EMT through c-Myc
  Naoya Inamura; Taichi Kimura; Lei Wang; Hiroko Yanagi; Masumi Tsuda; Mishie Tanino; Hiroshi Nishihara; Satoshi Fukuda; Shinya Tanaka
  AURIS NASUS LARYNX, 44, 4, 447, 457, 2017年08月, ［査読有り］
  英語, 研究論文（学術雑誌）
• PCTAIRE1/CDK16/PCTK1 is overexpressed in cutaneous squamous cell carcinoma and regulates p27 stability and cell cycle
  Teruki Yanagi; Hiroo Hata; Eri Mizuno; Shinya Kitamura; Keisuke Imafuku; Shinichi Nakazato; Lei Wang; Hiroshi Nishihara; Shinya Tanaka; Hiroshi Shimizu
  JOURNAL OF DERMATOLOGICAL SCIENCE, 86, 2, 149, 157, 2017年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Clinicopathological evaluation of Sox10 expression in diffuse-type gastric adenocarcinoma
  Marin Kato; Hiroshi Nishihara; Hideyuki Hayashi; Taichi Kimura; Yusuke Ishida; Lei Wang; Masumi Tsuda; Mishie Ann Tanino; Shinya Tanaka
  MEDICAL ONCOLOGY, 34, 1, 1, 8, 2017年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Analysis of NAB2-STAT6 Gene Fusion in 17 Cases of Meningeal Solitary Fibrous Tumor/Hemangiopericytoma: Review of the Literature.
  Yuzawa S; Nishihara H; Wang L; Tsuda M; Kimura T; Tanino M; Tanaka S
  The American journal of surgical pathology, 40, 8, 1031, 1040, 2016年08月, ［査読有り］
• Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells
  T. Kimura; L. Wang; K. Tabu; M. Tsuda; M. Tanino; A. Maekawa; H. Nishihara; H. Hiraga; T. Taga; Y. Oda; S. Tanaka
  ONCOGENE, 35, 30, 3932, 3943, 2016年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system
  Sayaka Yuzawa; Hiroshi Nishihara; Shigeru Yamaguchi; Hiromi Mohri; Lei Wang; Taichi Kimura; Masumi Tsuda; Mishie Tanino; Hiroyuki Kobayashi; Shunsuke Terasaka; Kiyohiro Houkin; Norihiro Sato; Shinya Tanaka
  MODERN PATHOLOGY, 29, 7, 708, 716, 2016年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Novel signaling collaboration between TGF-β and adaptor protein Crk facilitates EMT in human lung cancer.
  Elmansuri, AZ; Tanino, MA; Mahabir, R; Wang, L; Kimura, T; Nishihara, H; Kinoshita, I; Dosaka-Akita, H; Tsuda, M; Tanaka, S
  Oncotarget., 7, 19, 27094, 27107, 2016年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Rapid immunocytochemistry based on alternating current electric field using squash smear preparation of central nervous system tumors
  Jun Moriya; Mishie Ann Tanino; Tomoko Takenami; Tomoko Endoh; Masana Urushido; Yasutaka Kato; Lei Wang; Taichi Kimura; Masumi Tsuda; Hiroshi Nishihara; Shinya Tanaka
  BRAIN TUMOR PATHOLOGY, 33, 1, 13, 18, 2016年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Adaptor protein CRK induces epithelial-mesenchymal transition and metastasis of bladder cancer cells through HGF/c-Met feedback loop.
  Ryuji Matsumoto; Masumi Tsuda; Lei Wang; Nako Maishi; Takashige Abe; Taichi Kimura; Mishie Tanino; Hiroshi Nishihara; Kyoko Hida; Yusuke Ohba; Nobuo Shinohara; Katsuya Nonomura; Shinya Tanaka
  Cancer science, 106, 6, 709, 17, 2015年06月, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, We have previously reported that an adaptor protein CRK, including CRK-I and CRK-II, plays essential roles in the malignant potential of various aggressive human cancers, suggesting the validity of targeting CRK in molecular targeted therapy of a wide range of cancers. Nevertheless, the role of CRK in human bladder cancer with marked invasion, characterized by distant metastasis and poor prognosis, remains obscure. In the present study, immunohistochemistry indicated a striking enhancement of CRK-I/-II, but not CRK-like, in human bladder cancer tissues compared to normal urothelium. We established CRK-knockdown bladder cancer cells using 5637 and UM-UC-3, which showed a significant decline in cell migration, invasion, and proliferation. It is noteworthy that an elimination of CRK conferred suppressed phosphorylation of c-Met and the downstream scaffold protein Gab1 in a hepatocyte growth factor-dependent and -independent manner. In epithelial-mesenchymal transition-related molecules, E-cadherin was upregulated by CRK elimination, whereas N-cadherin, vimentin, and Zeb1 were downregulated. A similar effect was observed following treatment with c-Met inhibitor SU11274. Depletion of CRK significantly decreased cell proliferation of 5637 and UM-UC-3, consistent with reduced activity of ERK. An orthotopic xenograft model with bioluminescent imaging revealed that CRK knockdown significantly attenuated not only tumor volume but also the number of circulating tumor cells, resulted in a complete abrogation of metastasis. Taken together, this evidence uncovered essential roles of CRK in invasive bladder cancer through the hepatocyte growth factor/c-Met/CRK feedback loop for epithelial-mesenchymal transition induction. Thus, CRK might be a potent molecular target in bladder cancer, particularly for preventing metastasis, leading to the resolution of clinically longstanding critical issues.
• 肺高血圧症における血管病変の形態学的・免疫組織学的変化
  谷野 美智枝; 辻野 一三; 石田 雄介; 加藤 容崇; 王 磊; 木村 太一; 西原 広史; 田中 伸哉
  日本病理学会会誌, 104, 1, 311, 311, (一社)日本病理学会, 2015年03月
  日本語
• Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma
  Shinji Kohsaka; Kunihiko Hinohara; Lei Wang; Tatsunori Nishimura; Masana Urushido; Kazuhiro Yachi; Masumi Tsuda; Mishie Tanino; Taichi Kimura; Hiroshi Nishihara; Noriko Gotoh; Shinya Tanaka
  NEURO-ONCOLOGY, 16, 7, 960, 970, 2014年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Correction: microRNA 31 functions as an endometrial cancer oncogene by suppressing Hippo tumor suppressor pathway.
  Mitamura T; Watari H; Wang L; Kanno H; Miyazaki M; Kitagawa M; Hassan MK; Dong P; Kimura T; Tanino M; Nishihara H; Tanaka S; Sakuragi N
  Molecular cancer, 13, 140, 2014年06月, ［査読有り］
• Sustained elevation of Snail promotes glial-mesenchymal transition after irradiation in malignant glioma
  Roshan Mahabir; Mishie Tanino; Aiman Elmansuri; Lei Wang; Taichi Kimura; Tamio Itoh; Yusuke Ohba; Hiroshi Nishihara; Hiroki Shirato; Masumi Tsuda; Shinya Tanaka
  NEURO-ONCOLOGY, 16, 5, 671, 685, 2014年05月, ［査読有り］
  英語, 研究論文（学術雑誌）
• microRNA 31 functions as an endometrial cancer oncogene by suppressing Hippo tumor suppressor pathway
  Takashi Mitamura; Hidemichi Watari; Lei Wang; Hiromi Kanno; Makiko Kitagawa; Mohamed Kamel Hassan; Taichi Kimura; Mishie Tanino; Hiroshi Nishihara; Shinya Tanaka; Noriaki Sakuragi
  MOLECULAR CANCER, 13, 13, 97, 2014年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• NS1-binding protein abrogates the elevation of cell viability by the influenza A virus NS1 protein in association with CRKL
  Masaya Miyazaki; Hiroshi Nishihara; Hideki Hasegawa; Masato Tashiro; Lei Wang; Taichi Kimura; Mishie Tanino; Masumi Tsuda; Shinya Tanaka
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 441, 4, 953, 957, 2013年11月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Expression of CD163 prevents apoptosis through the production of granulocyte colony-stimulating factor in meningioma
  Hiromi Kanno; Hiroshi Nishihara; Lei Wang; Sayaka Yuzawa; Hiroyuki Kobayashi; Masumi Tsuda; Taichi Kimura; Mishie Tanino; Shunsuke Terasaka; Shinya Tanaka
  NEURO-ONCOLOGY, 15, 7, 853, 864, 2013年07月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Inhibition of GSH synthesis potentiates temozolomide-induced bystander effect in glioblastoma
  Shinji Kohsaka; Kenta Takahashi; Lei Wang; Mishie Tanino; Taichi Kimura; Hiroshi Nishihara; Shinya Tanaka
  CANCER LETTERS, 331, 1, 68, 75, 2013年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Relationship between Methyl CpG Binding Protein 2 and JC Viral Proteins
  Kenta Takahashi; Yasuko Orba; Taichi Kimura; Lei Wang; Shinji Kohsaka; Masumi Tsuda; Mishie Tanino; Hiroshi Nishihara; Kazuo Nagashima; Hirofumi Sawa; Shinya Tanaka
  JAPANESE JOURNAL OF INFECTIOUS DISEASES, 66, 2, 126, 132, 2013年03月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET
  T. Mitamura; H. Watari; L. Wang; H. Kanno; M. K. Hassan; M. Miyazaki; Y. Katoh; T. Kimura; M. Tanino; H. Nishihara; S. Tanaka; N. Sakuragi
  Oncogenesis, 2, 2, 40, 2013年, ［査読有り］
  英語, 研究論文（学術雑誌）
• STAT3 Inhibition Overcomes Temozolomide Resistance in Glioblastoma by Downregulating MGMT Expression
  Shinji Kohsaka; Lei Wang; Kazuhiro Yachi; Roshan Mahabir; Takuhito Narita; Tamio Itoh; Mishie Tanino; Taichi Kimura; Hiroshi Nishihara; Shinya Tanaka
  MOLECULAR CANCER THERAPEUTICS, 11, 6, 1289, 1299, 2012年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• CD133 Negatively Regulates Tumorigenicity via AKT Pathway in Synovial Sarcoma
  Taichi Kimura; Lei Wang; Kouichi Tabu; Hiroshi Nishihara; Yuji Mashita; Naoyuki Kikuchi; Mishie Tanino; Hiroaki Hiraga; Shinya Tanaka
  CANCER INVESTIGATION, 30, 5, 390, 397, 2012年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Prognostic Significance of Clusterin Expression in Advanced-Stage Cervical Cancer Treated With Curative Intended Radiotherapy
  Hidemichi Watari; Rumiko Kinoshita; Yimin Han; Lei Wang; Masayoshi Hosaka; Hiroshi Taguchi; Kazuhiko Tsuchiya; Shinya Tanaka; Hiroki Shirato; Noriaki Sakuragi
  INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, 22, 3, 465, 470, 2012年03月, ［査読有り］
  英語, 研究論文（学術雑誌）
• CRKL plays a pivotal role in tumorigenesis of head and neck squamous cell carcinoma through the regulation of cell adhesion
  Hiroko Yanagi; Lei Wang; Hiroshi Nishihara; Taichi Kimura; Mishie Tanino; Teruki Yanagi; Satoshi Fukuda; Shinya Tanaka
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 418, 1, 104, 109, 2012年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Clusterin is a potential molecular predictor for ovarian cancer patient's survival: targeting clusterin improves response to paclitaxel.
  Mohamed K Hassan; Hidemichi Watari; Yimin Han; Takashi Mitamura; Masayoshi Hosaka; Lei Wang; Shinya Tanaka; Noriaki Sakuragi
  Journal of experimental & clinical cancer research : CR, 30, 113, 113, 2011年12月20日, ［査読有り］, ［国際誌］
  英語, 研究論文（学術雑誌）, BACKGROUND: Clusterin is a cytoprotective chaperone protein involved in numerous physiological processes, carcinogenesis, tumor growth and tissue remodelling. The purpose of this study was to investigate whether clusterin (CLU), an antiapoptotic molecule, could be a potential predictor molecule for ovarian cancer and whether or not targeting this molecule can improve survival of ovarian cancer patients. METHODS: Clusterin expression was compared between ten primary and their recurrent tumors from same patients immunohistochemically. We analyzed prognostic significance of CLU expression in another 47 ovarian cancer tissue samples by immunohistochemistry. We used small interference RNA to knock down CLU in the chemo-resistant ovarian cancer cell lines. KF-TX and SKOV-3-TX, paclitaxel-resistant ovarian cancer cells, were established from parental KF and SKOV-3 chemo-sensitive cell lines, respectively. Either siRNA or second generation antisense oligodeoxynucleotide against CLU (OGX-011), which is currently evaluated in clinical phase II trials in other cancer s, was used to modulate sensitivity to paclitaxel (TX) in ovarian cancer cells in vitro. Cellular viability assay, FACS analysis and annexin V staining were used to evaluate the comparative effect of CLU knocking down in ovarian cancer cells. RESULTS: Immunohistochemical analysis of CLU expression in primary ovarian cancer tissue specimens and their recurrent counterparts from same patients demonstrated higher expression of CLU in the recurrent resistant tumors compared with their primary tumors. High expression of CLU by immunohistochemistry among 47 surgical tissue specimens of early-stage (stage I/II) ovarian cancer, who underwent complete cytoreduction as a primary surgery, significantly related to poor survival, while none of other clinicopathological factors analyzed were related to survival in this patient cohort. Secretory CLU (s-CLU; 60 KDa) expression was upregulated in TX-resistant ovarian cancer cells compared to parental cells. Transfection of siRNA or OGX-011 clearly reduced CLU expression. Cell viability assay, FACS analysis and annexin V staining demonstrated that targeting CLU expression by siRNA or OGX-011 sensitized ovarian cancer cells to TX. CONCLUSION: We conclude that CLU could be a potential molecular target to predict survival while targeting this s-CLU may improve survival of patients with ovarian cancer.
• Clusterin is a potential molecular predictor for ovarian cancer patient's survival: targeting Clusterin improves response to paclitaxel
  Mohamed K. Hassan; Hidemichi Watari; Yimin Han; Takashi Mitamura; Masayoshi Hosaka; Lei Wang; Shinya Tanaka; Noriaki Sakuragi
  JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 30, 2011年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Clinicopathologic application of lectin histochemistry: Bisecting GlcNAc in glioblastoma
  Eiko Aoyanagi; Ken Sasai; Ken Sasai; Miho Nodagashira; Lei Wang; Hiroshi Nishihara; Hideyuki Ihara; Yoshitaka Ikeda; Shinya Tanaka
  Applied Immunohistochemistry and Molecular Morphology, 18, 518, 525, 2010年12月, ［査読有り］
  英語, Glycosylation is one of the most common posttranslational modifications and changes in oligosaccharide structures are associated with many human diseases including a number of cancers. Thus, discovering aberrant glycosylation patterns that serve as markers for brain tumor progression and metastasis represents an attractive strategy to improve clinicopathologic diagnosis and to provide aids to the development of novel therapies. To identify glioblastoma (GBM) cells expressing glycoproteins that contain high levels of the bisecting N-acetylglucosamine (GlcNAc) structures, lectin histochemistry was carried out using erythroagglutinating phytohemagglutinin. Although GBM frequently expressed the bisecting GlcNAc, the lectin reactivity varied among tumor regions within individual specimens. Since detailed histopathologic analysis revealed that oligosaccharides with bisecting GlcNAc structures were preferably expressed in tumor regions with low KI67 immunopositivity, immunodetection of the bisecting GlcNAc could be useful to indicate less proliferative regions in human GBM. Our study highlights the potential use of lectin histochemistry to develop new methods for diagnosis that would impr
• DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma
  Lei Wang; Hiroshi Nishihara; Taichi Kimura; Yasutaka Kato; Mishie Tanino; Mitsufumi Nishio; Masato Obara; Tomoyuki Endo; Takao Koike; Shinya Tanaka
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 395, 1, 111, 115, 2010年04月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks
  Kouichi Tabu; Taichi Kimura; Ken Sasai; Lei Wang; Norihisa Bizen; Hiroshi Nishihara; Tetsuya Taga; Shinya Tanaka
  MOLECULAR CANCER, 9, 39, 2010年02月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Sudden Death of a Patient with Pandemic Influenza (A/H1N1pdm) Virus Infection by Acute Respiratory Distress Syndrome
  Akihiro Takiyama; Lei Wang; Mishie Tanino; Taichi Kimura; Naoki Kawagishi; Yasuyuki Kunieda; Harutaka Katano; Noriko Nakajima; Hideki Hasegawa; Tomoyuki Takagi; Hiroshi Nishihara; Tetsutaro Sata; Shinya Tanaka
  JAPANESE JOURNAL OF INFECTIOUS DISEASES, 63, 1, 72, 74, 2010年01月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Human synovial sarcoma proto-oncogene Syt is essential for early embryonic development through the regulation of cell migration
  Taichi Kimura; Mieko Sakai; Kouichi Tabu; Lei Wang; Ryosuke Tsunematsu; Masumi Tsuda; Hirofumi Sawa; Kazuo Nagashima; Hiroshi Nishihara; Shigetsugu Hatakeyama; Keiko Nakayama; Marc Ladanyi; Shinya Tanaka; Keiichi I. Nakayama
  LABORATORY INVESTIGATION, 89, 6, 645, 656, 2009年06月, ［査読有り］
  英語, 研究論文（学術雑誌）
• CNS lymphomatoid granulomatosis with lymph node and bone marrow involvements
  Akihiro Takiyama; Hiroshi Nishihara; Ukihide Tateishi; Taichi Kimura; Wang Lei; Katsuji Marukawa; Tomoo Itoh; Satoshi Hashino; Kazuo Nagashima; Shinya Tanaka
  NEUROPATHOLOGY, 28, 6, 640, 644, 2008年12月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Promoter hypomethylation regulates CD133 expression in human gliomas
  Kouichi Tabu; Ken Sasai; Taichi Kimura; Lei Wang; Eiko Aoyanagi; Shinji Kohsaka; Mishie Tanino; Hiroshi Nishihara; Shinya Tanaka
  CELL RESEARCH, 18, 10, 1037, 1046, 2008年10月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Establishment of a luciferase assay-based screening system: Fumitremorgin C selectively inhibits cellular proliferation of immortalized astrocytes expressing an active form of AKT
  Lei Wang; Ken Sasai; Tsuyoshi Akagi; Shinya Tanaka
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 373, 3, 392, 396, 2008年08月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O-6-methylguanine-DNA methyltransferase status in glioma - Relationship between immunohistochemistry and methylation analysis
  Ken Sasai; Miho Nodagashira; Hiroshi Nishihara; Eiko Aoyanagi; Lei Wang; Masahito Katoh; Junichi Murata; Yoshimaru Ozaki; Tamio Ito; Shin Fujimoto; Sadao Kaneko; Kazuo Nagashima; Shinya Tanaka
  AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 32, 8, 1220, 1227, 2008年08月, ［査読有り］
  英語, 研究論文（学術雑誌）
• Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4
  Lei Wang; Kouichi Tabu; Taichi Kimura; Masumi Tsuda; Hua Linghu; Mishie Tanino; Sadao Kaneko; Hiroshi Nishihara; Shinya Tanaka
  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 362, 4, 976, 981, 2007年11月, ［査読有り］
  英語, 研究論文（学術雑誌）

• 合成高分子ハイドロゲルを用いた白血病新規治療標的分子の探索
  小田義崇; 津田真寿美; 津田真寿美; WANG Lei; WANG Lei; 田中伸哉; 田中伸哉; 田中伸哉, 日本がん分子標的治療学会学術集会プログラム・抄録集, 29th, 2025年
• アダプター分子Crkは神経芽腫におけるハイドロゲル誘導がん幹細胞性に必須である
  宮本裕也; 津田真寿美; 津田真寿美; 王磊; 王磊; 小田義崇; 種井善一; 種井善一; きょう剣萍; きょう剣萍; 田中伸哉; 田中伸哉; 田中伸哉, 日本分子生物学会年会プログラム・要旨集(Web), 48th, 2025年
• 膠芽腫におけるCOL6A2発現グリオーマ幹細胞と微小血管増生との関連解析
  高村敦子; 津田真寿美; 津田真寿美; 王磊; 王磊; 小田義崇; 種井善一; 種井善一; きょう剣萍; きょう剣萍; 田中伸哉; 田中伸哉; 田中伸哉, 日本分子生物学会年会プログラム・要旨集(Web), 48th, 2025年
• 脳腫瘍の細胞像と病理像
  種井善一; 小田義崇; 王磊; 王磊; 津田真寿美; 津田真寿美; 田中伸哉; 田中伸哉, 日本臨床細胞学会雑誌(Web), 63, 2024年
• ハイドロゲル上で誘導された膀胱癌幹細胞の特徴と標的治療の探索。
  王磊; 王磊; 津田真寿美; 津田真寿美; 小田義崇; 田中伸哉; 田中伸哉; 田中伸哉, 日本癌学会学術総会抄録集(Web), 83rd, 2024年
• 微小血管増生ニッシェに潜伏するグリオーマ幹細胞を標的とした治療戦略
  津田真寿美; 津田真寿美; 王磊; 王磊; 小田義崇; 田中伸哉; 田中伸哉, 日本癌学会学術総会抄録集(Web), 83rd, 2024年
• ハイドロゲル誘導グリオーマ幹細胞におけるCOL6A2の機能解析
  高村敦子; 高村敦子; 津田真寿美; 津田真寿美; 王磊; 王磊; 小田義崇; 種井善一; 種井善一; きょう剣萍; きょう剣萍; 田中伸哉; 田中伸哉; 田中伸哉, 日本分子生物学会年会プログラム・要旨集(Web), 47th, 2024年
• Artificial Intelligence Predicts the Genetic Information of The Integrated Diagnosis of Brain Tumors
  Yusuke Ishida; Masumi Tsuda; Jun Suzuka; Lei Wang; Satoshi Tanikawa; Hirokazu Sugino; Shinya Tanaka, MODERN PATHOLOGY, 32, 2019年03月
  英語, 研究発表ペーパー・要旨（国際会議）
• Artificial Intelligence Predicts the Genetic Information of The Integrated Diagnosis of Brain Tumors
  Yusuke Ishida; Masumi Tsuda; Jun Suzuka; Lei Wang; Satoshi Tanikawa; Hirokazu Sugino; Shinya Tanaka, LABORATORY INVESTIGATION, 99, 2019年03月
  英語, 研究発表ペーパー・要旨（国際会議）
• Development of bipolar charged hydrogel for neuronal tissue engineering
  Satoshi Tanikawa; Shingo Semba; Lei Wang; Mishie Tanino; Yusuke Ishida; Hirokazu Sugino; Jun Suzuka; Masumi Tsuda; Shinya Tanaka, BRAIN PATHOLOGY, 29, 109, 109, 2019年02月
  英語, 研究発表ペーパー・要旨（国際会議）
• IDH1 Mutation Enhances Radiation Sensitivity by Regulating EMT and Apoptotic Pathway in Malignant Glioma
  Mishie A. Tanino; Arisa Kitazaki; Mei Kuzasa; Hirokazu Sugino; Yusuke Ishida; Lei Wang; Masumi Tsuda; Shinya Tanaka, MODERN PATHOLOGY, 31, 667, 667, 2018年03月
  英語, 研究発表ペーパー・要旨（国際会議）
• IDH1 Mutation Enhances Radiation Sensitivity by Regulating EMT and Apoptotic Pathway in Malignant Glioma
  Mishie A. Tanino; Arisa Kitazaki; Mei Kuzasa; Hirokazu Sugino; Yusuke Ishida; Lei Wang; Masumi Tsuda; Shinya Tanaka, LABORATORY INVESTIGATION, 98, 667, 667, 2018年03月
  英語, 研究発表ペーパー・要旨（国際会議）
• 低分化胃癌におけるSox10発現の臨床病理学的検討
  石川 麻倫; 西原 広史; 林 秀幸; 木村 太一; 石田 雄介; 王 磊; 津田 真寿美; 谷野 美智枝; 坂本 直哉; 田中 伸哉, 日本消化器病学会雑誌, 115, 臨増総会, A375, A375, 2018年03月
  (一財)日本消化器病学会, 日本語
• IDH1 mutation contributes to apoptosis after multi-fractionated irradiation in malignant glioma
  Arisa Kitazaki; Mishie Tanino; Mei Kuzasa; Hirokazu Sugino; Lei Wang; Yusuke Ishida; Shingo Semba; Masumi Tsuda; Kaori Igarashi; Tomoyoshi Soga; Shinya Tanaka, CANCER SCIENCE, 109, 1130, 1130, 2018年01月
  英語, 研究発表ペーパー・要旨（国際会議）
• Expression of OTUB1 in human malignant mesothelioma
  Mei Kuzasa; Mishie Tanino; Arisa Kitazaki; Hirokazu Sugino; Yusuke Ishida; Lei Wang; Masumi Tsuda; Akira Takasawa; Hiroshi Hirano; Shinya Tanaka, CANCER SCIENCE, 109, 1109, 1109, 2018年01月
  英語, 研究発表ペーパー・要旨（国際会議）
• 卵巣明細胞腺癌に対するcabozantinibの抗腫瘍効果についての検討
  中谷 真紀子; 渡利 英道; 王 磊; 畑中 豊; 畑中 佳奈子; 西原 広史; 朝野 拓史; 遠藤 大介; 三田村 卓; 董 培新; シャロン・ハンリー; 田中 伸哉; 櫻木 範明, 日本婦人科腫瘍学会雑誌, 35, 3, 628, 628, 2017年06月
  (公社)日本婦人科腫瘍学会, 日本語
• miR-23aによる膠芽腫の浸潤能亢進分子メカニズムの解明
  津田 真寿美; 谷地 一博; 高阪 真路; 三浪 友輔; 王 磊; 木村 太一; 谷野 美智枝; 西原 広史; 田中 伸哉, Brain Tumor Pathology, 34, Suppl., 093, 093, 2017年05月
  日本脳腫瘍病理学会, 日本語
• 原発不明癌症例の臨床病理学的解析
  高田 莉央; 鈴木 喬之; 谷野 美智枝; 木村 太一; 石田 雄介; 王 磊; 西原 広史; 田中 伸哉; 篠原 敏也; 後藤田 裕子, 日本病理学会会誌, 106, 1, 511, 511, 2017年03月
  (一社)日本病理学会, 日本語
• GENOTYPING OF GLIOMA INCLUDING 1p19q CODELETION BY TARGETED SEQUENCING
  Hiroshi Nishihara; Shigeki Tanishima; Sayaka Yuzawa; Lei Wang; Shigeru Yamaguchi; Hiroyuki Kobayashi; Shunsuke Terasaka; Shinya Tanaka, NEURO-ONCOLOGY, 18, 118, 118, 2016年11月
  英語, 研究発表ペーパー・要旨（国際会議）
• チロシンキナーゼ阻害剤耐性膠芽腫細胞における腫瘍幹細胞性獲得とSFRP1の関連性
  鈴鹿 淳; 津田 真寿美; 王 磊; 谷野 美智枝; 木村 太一; 西原 広史; 田中 伸哉, 日本癌学会総会記事, 75回, J, 2036, 2016年10月
  日本癌学会, 英語
• 肺癌においてアダプター蛋白CrkはTGF-βシグナルと協調してEMTを誘導する
  谷野 美智枝; Elimansuri Aiman; Mahabir Roshan; 王 磊; 木村 太一; 西原 広史; 津田 真寿美; 田中 伸哉, 日本癌学会総会記事, 75回, P, 1092, 2016年10月
  日本癌学会, 英語
• 髄膜発生SFT/HPCのNAB2-STAT6融合遺伝子パターンと臨床病理学的検討
  湯澤 明夏; 西原 広史; 王 磊; 津田 真寿美; 木村 太一; 谷野 美智枝; 田中 伸哉, Brain Tumor Pathology, 33, Suppl., 102, 102, 2016年05月
  日本脳腫瘍病理学会, 日本語
• 臨床的シークエンス分析による髄膜腫の予後的影響(Prognostic impact for meningioma by clinical sequence system)
  湯澤 明夏; 西原 広史; 山口 秀; 毛利 普美; 王 磊; 木村 太一; 津田 真寿美; 谷野 美智枝; 佐藤 典宏; 田中 伸哉, 日本病理学会会誌, 105, 1, 356, 356, 2016年04月
  (一社)日本病理学会, 英語
• CRKアダプター蛋白質はHGF/c-Metフィードバックループを介して膀胱癌のEMTと転移を誘導する
  王 磊; 松本 隆児; 津田 真寿美; 間石 奈湖; 安部 崇重; 木村 太一; 谷野 美智枝; 西原 広史; 樋田 京子; 大場 雄介; 篠原 信雄; 田中 伸哉, 日本癌学会総会記事, 74回, J, 1142, 2015年10月
  日本癌学会, 英語
• 胃低分化腺癌及び印環細胞癌におけるactionable mutationの網羅的検討
  石川麻倫; 石川麻倫; 西原広史; 毛利普美; 毛利普美; 加藤容崇; WANG Lei; 木村太一; 津田真寿美; 谷野美智枝; 田中伸哉; 田中伸哉, 日本病理学会会誌, 104, 1, 2015年
• Novel somatic and germline mutations in intracranial germ cell tumours.
  Wang L; Yamaguchi S; Burstein MD; Terashima K; Chang K; Ng HK; Nakamura H; He Z; Doddapaneni H; Lewis L; Wang M; Suzuki T; Nishikawa R; Natsume A; Terasaka S; Dauser R; Whitehead W; Adekunle A; Sun J; Qiao Y; Marth G; Muzny DM; Gibbs RA; Leal SM; Wheeler DA; Lau CC, Nature, 511, 7508, 241, 2014年07月10日, ［査読有り］
  英語, 速報，短報，研究ノート等（学術雑誌）
• The mesenchymal phenotype in recurrent glioblastoma is due to irradiation induced Snail expression and resultant EMT.
  Roshan Mahabir; Mishie Tanino; Aiman Elmansuri; Masumi Tsuda; Taichi Kimura; Lei Wang; Hiroshi Nishihara; Shinya Tanaka, MOLECULAR CANCER THERAPEUTICS, 12, 11, 2013年11月
  英語, 研究発表ペーパー・要旨（国際会議）
• 消化器癌におけるERC/Mesothelinの分子病理学的検討(Molecular and clinicopathological analysis for ERC/Mesothelin in digestive cancers)
  西原 広史; 川俣 太; 永生 高広; 津田 真寿美; 王 磊; 樋野 興夫; 武冨 紹信; 田中 伸哉, 日本癌学会総会記事, 72回, 308, 308, 2013年10月
  日本癌学会, 英語
• グリオブラストーマにおいてSTAT3阻害はMGMTを発現低下させることで抗がん剤 Temozolomide 耐性を解除する
  高阪 真路; 王 磊; 谷地 一博; 成田 拓人; 木村 太一; 谷野 美智枝; 西原 広史; 田中 伸哉, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 87, 4, 209, 209, 2012年08月01日
  日本語
• 髄膜腫におけるCD163の発現と機能解析
  菅野宏美; 西原広史; 王磊; 木村太一; 谷野美智枝; 田中伸哉; 田中伸哉, 日本病理学会会誌, 101, 1, 246, 2012年03月26日
  日本語, その他
• GliomaにおけるMGMT発現調節による抗癌剤耐性解除の可能性の検討
  高阪真路; 王磊; 谷地一博; 成田拓人; 木村太一; 谷野美智枝; 西原広史; 田中伸哉, 日本病理学会会誌, 100, 1, 349, 2011年03月26日
  日本語, その他
• 疾患形成における標的分子の役割 急激な経過で死亡した新型インフルエンザ肺炎症例の病理学的検討
  瀧山晃弘; Wang Lei; 谷野美智枝; 木村太一; 西原広史; 田中伸哉, 分子呼吸器病, 15, 1, 132-136, 2011年03月01日
  日本語, その他
• B型肝硬変に合併し、肝膿瘍との鑑別に苦慮した肝癌の1例
  中積 宏之; 高阪 真路; 王 磊, 岩見沢市立総合病院医誌, 36, 1, 89, 90, 2010年06月
  岩見沢市立総合病院, 日本語
• シグナル伝達分子のImmunoprofiling;胃癌20例における臨床病理学的検討
  石川麻倫; 大場彩音; 西原広史; 菅野宏美; 王磊; 木村太一; 谷野美智枝; 田中伸哉; 田中伸哉, 日本病理学会会誌, 99, 1, 369, 369, 2010年03月26日
  (一社)日本病理学会, 日本語, その他
• 新型インフルエンザ(A/H1N1pdm)肺炎によるびまん性肺胞傷害により急死した1剖検例
  瀧山晃弘; 王磊; 谷野美智枝; 木村太一; 西原広史; 川岸直樹; 國枝保幸; 片野晴隆; 長谷川秀樹; 高木知敬; 佐多徹太郎; 田中伸哉; 田中伸哉, 日本病理学会会誌, 99, 1, 297, 2010年03月26日
  日本語, その他
• 捺印標本を用いたグリオーマのMGMT免疫染色の検討
  青柳瑛子; 王磊; 笹井研; 谷野美智枝; 木村太一; 西原広史; 藤本真; 石井伸明; 伊東民雄; 田中伸哉; 田中伸哉, 日本臨床細胞学会雑誌, 49, 220, 2010年03月22日
  日本語, その他
• CNS lymphomatoid granulomatosis with lymph node and bone marrow involvements. (vol 28, pg 640, 2008)
  A. Takiyama; H. Nishihara; U. Tateishi; T. Kimura; W. Lei; K. Marukawa; T. Itoh; S. Hashino; K. Nagashima; S. Tanaka, NEUROPATHOLOGY, 29, 4, 520, 520, 2009年08月
  英語, その他
• 悪性胸膜中皮腫におけるシグナル伝達アダプター分子CRKを介したRac活性の可視化
  谷野美智枝; 王磊; 津田真寿美; 西原広史; 大場雄介; 矢野聖二; 曽根三郎; 田中伸哉, 日本呼吸器学会雑誌, 47, 237, 2009年05月10日
  日本語, その他
• 滑膜肉腫細胞株におけるCD133の機能解析
  木村太一; 王磊; 平賀博明; 西原広史; 田中伸哉, 日本病理学会会誌, 98, 1, 391, 2009年03月20日
  日本語, その他
• N型糖鎖のbisectin GlcNAc構造は膠芽腫においてMIB1インデックスが低い領域に高発現する
  青柳瑛子; 笹井研; WANG Lei; 野田頭未歩; 西原広史; 田中伸哉; 田中伸哉, 日本病理学会会誌, 98, 1, 300, 2009年03月20日
  日本語, その他
• DOCK180はHodgkin細胞に発現し,細胞の形態制御に重要な役割を果たしている
  王磊; 西原広史; 西原広史; 田中伸哉; 田中伸哉, 日本病理学会会誌, 98, 1, 276, 2009年03月20日
  日本語, その他
• Involvement of Adaptor Protein Crk in Malignant Features of Human Mesothelioma.
  M. A. Tanino; L. Wang; S. Kohsaka; T. Kimura; K. Sasai; H. Nishihara; M. Tsuda; S. Yano; S. Tanaka, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179, 2009年
  英語, 研究発表ペーパー・要旨（国際会議）
• 胸膜中皮腫におけるシグナル伝達アダプター分子CRKの役割の解析
  谷野美智枝; 王磊; 西原広史; 松野吉宏; 矢野聖二; 曽根三郎; 田中伸哉, 日本呼吸器学会雑誌, 46, 289, 2008年05月10日
  日本語, その他
• 悪性膠腫におけるCD133発現の分子細胞病理学的解析
  椨康一; 笹井研; 木村太一; 谷野美智枝; 青柳瑛子; 王磊; 高阪真路; 西原広史; 田中伸哉, 日本病理学会会誌, 97, 1, 244, 2008年03月31日
  日本語, その他
• 悪性膠腫におけるMGMT発理の病理組織学的解析
  野田頭未歩; 青柳瑛子; 笹井研; 王磊; 西原広史; 長嶋和郎; 田中伸哉, 日本病理学会会誌, 97, 1, 244, 2008年03月31日
  日本語, その他
• DOCK180 is induced with differentiation from CD14 positive monocytes and it regulates phagocytosis in both macrophages and dendritic cells.
  K Fujimoto; M Nishio; H Nishihara; Sato, I; L Wang; S Tanaka; T Koike, BLOOD, 106, 11, 861A, 861A, 2005年11月
  英語, 研究発表ペーパー・要旨（国際会議）

• ハイドロゲルを用いた新規膀胱癌幹細胞誘導・維持技術の確立と癌治療への基盤確立
  科学研究費助成事業
  2025年04月01日 - 2028年03月31日
  王 磊; 松本 隆児
  日本学術振興会, 基盤研究(C), 北海道大学, 25K08759
• Tリンパ球におけるPRDM1遺伝子多型と抗腫瘍免疫機能との相関に関する基礎的研究
  科学研究費助成事業
  2025年04月01日 - 2028年03月31日
  三田村 卓; 渡利 英道; サイ テンゲツ; 王 磊
  日本学術振興会, 基盤研究(C), 北海道大学, 25K10483
• 一軸配向化合成コラーゲン線維が誘導する骨髄幹細胞の分化と基質産生促進機序の解明
  科学研究費助成事業
  2022年04月01日 - 2025年03月31日
  近藤 英司; 津田 真寿美; 王 磊; 柚木 俊二
  研究代表者は先行する研究において、生体に無細胞化した腱組織(一軸配向コラーゲン線維束)を移植すると、そこへ侵入した間葉系幹細胞(MSC)が腱・靱帯線維芽細胞に分化し、I型コラーゲンを含む細胞外マトリクス(ECM)が豊富に産生されて腱・靱帯組織が再生されることを発見した。しかし何がMSCの分化を開始させるのか、その分子機序は未だ解明されていない。研究代表者らは、独自の研究結果と様々な配向化材料が有する対細胞効果に関する世界の研究に基づき、「移植した一軸配向コラーゲンのcomposition and organization (構成と組織構造)が、そこに接着するMSCの腱性線維芽細胞への分化とECM関連遺伝子の発現を誘導し、腱性基質産生を促進する」という仮説を立てた。本研究の目的はこの仮説を証明することである。
  我々が独自に開発したコラーゲンの延伸紡糸法により、生体腱を構成するコラーゲンファイバー（直径～20micrometer）に比肩する細さを有し、線維が表層のみならず内部まで配向したコラーゲンMFの高速成型に成功した。この配向コラーゲンMFを束にした合成コラーゲン人工腱は湿潤状態でヒトACL(接線弾性率：283±114MPa、破断応力：45.7±19.5MPa)の約半値(137±7 MPaおよび13.8±1.9 MPa)に達し、実用的なレベルへと到達した。家兎膝蓋腱モデルを用いたin vivo評価により、ファイバー間隙が細胞浸潤を促し、埋植後16日で表層から徐々に生分解を受ける生体内安定性を示すことが明らかになった。延伸紡糸で作製したコラーゲンMFの太さ、架橋度、および緻密性は制御可能であり、理想的な合成コラーゲン人工腱を創製する道が拓けた。
  日本学術振興会, 基盤研究(B), 北海道大学, 23K25172
• 一軸配向化合成コラーゲン線維が誘導する骨髄幹細胞の分化と基質産生促進機序の解明
  科学研究費助成事業
  2022年04月01日 - 2025年03月31日
  近藤 英司; 柚木 俊二; 津田 真寿美; 王 磊
  日本学術振興会, 基盤研究(B), 北海道大学, 22H03918
• 多孔性高機能ハイドロゲルを用いたin vitro3D神経膠芽腫組織の創出
  科学研究費助成事業
  2021年04月01日 - 2024年03月31日
  王 磊; 谷川 聖
  悪性脳腫瘍（神経膠芽腫Glioblastoma, GBM）は治療抵抗性が高く、再発が多く、5年生存率は8%以下と予後が極めて悪い。治療抵抗性と再発はGBMのがん幹細胞（GBM stem cell, GSC）が再増殖するため、GSCの性質を知り、特異的に標的とする治療法の開発が必要である。しかしながら、GSCはがん組織中に微量であり、症例ごとにマーカーも異なり、同一組織の中で多様性があるため研究論文は多数あるが、実臨床での治療標的には至っていない。申請者らは、北大オリジナル高機能高分子ソフト＆ウェットマター（以下、高機能ハイドロゲル）を用いて高速・効率的ながん幹細胞の誘導法を開発した。本研究はこの誘導法を発展させて、Porous化した高機能ハイドロゲルを用いて、GSCニッシェを創出することで、ヒトの脳内病変を模倣したGBM組織を再構築する。そしてニッシェがGSCを制御・維持するしくみを解明し、それに基づくGSCに特異的な治療法の開発を目指す。昨年度血管内皮及び周皮細胞を用いた血管網の構築に最適なPorous高機能ハイドロゲルの創出について：ゲルの物理特性として、力学的性質および電荷密度の2点に着目した。力学的にハイドロゲルは生体軟組織と同程度の弾性率を有し、弾性率は調製可能なため、引張試験・動的粘弾性試験により培養基盤の粘弾性的性質を定量化した。物理因子を調節することで目的に血管内皮及び周皮細胞に対して最適な高機能ゲルを作成した。HEMA濃度の調整で、最適なporeサイズ（5~20μm）を探し出した。血管内皮及び周皮細胞に対して最適な培養する高機能ゲルを見出した。また、数種類の神経膠腫培養細胞株を高機能ハイドロゲル上で培養すると幹細胞様sphereを形成し、幹細胞マーカーSox2、Oct3/4、Nanogが短時間で発現亢進することを見出した。これら細胞を用いて、血管内皮及び周皮細胞を導入したPorous化高機能ハイドロゲル上の3D培養を試みる予定です。
  日本学術振興会, 基盤研究(C), 北海道大学, 21K12679
• 一軸配向化高靱性合成コラーゲンゲル線維束の生体内再構築に関する適応制御機序の解明
  科学研究費助成事業
  2019年04月01日 - 2022年03月31日
  近藤 英司; 安田 和則; 柚木 俊二; 王 磊
  独自の方法(特開2016-077411、特願2017-215184)を用いて、一軸配向化高靱性コラーゲン線維束を合成し、それを3次元化して合成腱マトリクスを作製した。また比較対照として、既に確立した方法を用いて天然腱マトリクスおよび完全緻密性コラーゲンを作製した。それらを家兎の関節外における生理的負荷環境に移植し、再構築過程を生体力学的および組織学的に比較した。一軸配向化高靱性合成コラーゲンゲル線維束では線維方向に細胞配向性が観察された。一部は経時的に吸収され、腱組織への置換が観察されたことより生体内再構築が生じたことが示唆された。
  日本学術振興会, 基盤研究(C), 北海道大学, 19K12746
• 癌の転移先臓器決定と覚醒におけるCrkおよびExosomeの機能解析
  科学研究費助成事業
  2018年04月01日 - 2021年03月31日
  津田 真寿美; 田中 伸哉; 王 磊
  本研究により、アダプター分子Crkはエクソソームの内包分子の種類と量を制御しており、Crk高発現膀胱癌細胞由来のエクソソームにはCrkとともにErbB2が含まれ、これが転移先臓器の肺の血管内皮細胞に作用し、膀胱癌細胞の肺転移を促進することが明らかになった。このことは、エクソソームに内包されているCrkやErbB2が転移先臓器のレシピエント細胞のシグナル伝達経路を活性化してその形質を変化させていることを示唆する。Crkを高発現しているがんは数多く報告されており、これによりエクソソームの内包分子についてもヘテロジェナイティーが創出され、がんの転移の選択と成立に寄与している可能性が示唆された。
  日本学術振興会, 基盤研究(C), 北海道大学, 18K07059
• 画像と病理情報の融合によるMRI-based PathoViewの構築
  科学研究費助成事業
  2015年04月01日 - 2017年03月31日
  西原 広史; 青木 伊知男; 王 磊; 瀧山 晃弘
  本研究の目的は、マウス肝臓の全包埋病理切片を用いて、空間分解能が0.05mmの高磁場MRIと病理像を統合し、Google Mapにおけるストリートビューのほうなマルチスケールの病理画像システムを構築することである。
  H27-28年度にかけて、マウス肝臓の全包埋連続切片1000枚を作製し、組織膨張の関係などから、作成切片の間引きの設定など、細かな条件検討を実施した研究条件の最適化を行った。現在、こうした条件に基づいた連続切片のHE染色を終了し、血管像との位置合わせを行ったうえで、バーチャルスライドデータとしての取り込みを完了した。今後は、画像統合、３D化、数理プログラム開発に挑戦する予定である。
  日本学術振興会, 挑戦的萌芽研究, 北海道大学, 15K15207