Research activity information

• Photoswitchable agonists for visible-light activation of the Wnt signaling pathway.
  Shifa Ahmad; P K Hashim; Masamichi Imajo; Nusaiba Madappuram Cheruthu; Kiyonori Takahashi; Shinya Tanaka; Takayoshi Nakamura; Nobuyuki Tamaoki
  Organic & biomolecular chemistry, 23, 17, 4240, 4245, 30 Apr. 2025, [International Magazine]
  English, Scientific journal, Based on the known Wnt agonist BML-284, we designed and synthesized photoswitchable azo derivative compounds that can act as agonists for the Wnt signaling pathway. These photoswitchable agonists were shown to undergo reversible trans-cis isomerization upon being irradiated with visible light, but only the cis isomer was observed to activate the Wnt signaling pathway, using a luminescense-based reporter assay in cultured cells. One of the compounds, denoted as compound 2, showed ∼88% agonist activity after being subjected to visible light irradiation in comparison to the non-photoswitchable BML-284. We also were able to selectively activate the Wnt signaling pathway using 2 and light irradiation at a specific region of interest in a model cell culture system, highlighting the ability to achieve spatiotemporal regulation.
• Establishment of a novel mouse model of colorectal cancer by orthotopic transplantation
  Cewen Chen; Qiaochu Fu; Lei Wang; Shinya Tanaka; Masamichi Imajo
  BMC Cancer, 06 Mar. 2025
  English, Scientific journal, Abstract
  
  Background
  Colorectal cancer (CRC) represents a major malignancy that poses a significant threat to human health worldwide. The establishment of a reliable and pathologically relevant orthotopic model of CRC is crucial for gaining a deeper understanding of its molecular mechanisms and for developing more effective therapies. Nonetheless, the development of such models is fraught with challenges primarily owing to the technical complexities associated with the transplantation of CRC cells into the intestinal epithelium.
  
  
  Methods
  The luminal surface of the cecum was externalized to visualize the entire process involved in the transplantation of CRC cells into the cecal epithelium of BALB/c athymic nude mice. The cecal epithelium was mechanically removed, preserving the integrity of the submucosal layer. Caco-2 CRC cells were subsequently inoculated onto the epithelium-depleted surface of the cecum to reproduce the development of CRC within the epithelial layer. The successful removal of the epithelium and transplantation of Caco-2 cells were verified through the use of appropriate fluorescent labeling techniques and examination with a fluorescence stereoscopic microscope.
  
  
  Results
  Following orthotopic transplantation, Caco-2 cells formed tumors in the cecum, where tumors progressed from a flat monolayer epithelium to thickened aberrant crypt foci, and then to protruding polyps, aided by mesenchymal cells infiltrating the tumors to form a stalk region, and eventually to large tumors invading the submucosa. Throughout this process, Caco-2 cells retained stem cell and fetal intestinal signatures, regardless of their location within the tumors or their proliferative status. Histopathological analysis further suggested that interactions between the transplanted Caco-2 cells and the surrounding normal epithelial and mesenchymal cells play critical roles in tumor development and in the elimination of normal epithelial cells from the tumor in this model.
  
  
  Conclusions
  This study established a novel orthotopic model of CRC within the mouse cecum. Tumor development and progression in this model include sequential morphological changes from a flat monolayer to large invasive tumors. The establishment of this orthotopic CRC model, which mimics tumor development in a more natural microenvironment, provides new opportunities to investigate the molecular mechanisms underlying CRC and to evaluate novel anticancer therapies in pathologically relevant contexts.
  
• Generation of Fetal Intestinal Organoids and Their Maturation into Adult Intestinal Cells
  Masamichi Imajo; Akira Hirota; Shinya Tanaka
  Methods in Molecular Biology, 2650, 133, 140, Jun. 2023
  In book
• Engineering of an electrically charged hydrogel implanted into a traumatic brain injury model for stepwise neuronal tissue reconstruction
  Satoshi Tanikawa; Yuki Ebisu; Tomáš Sedlačík; Shingo Semba; Takayuki Nonoyama; Takayuki Kurokawa; Akira Hirota; Taiga Takahashi; Kazushi Yamaguchi; Masamichi Imajo; Hinako Kato; Takuya Nishimura; Zen ichi Tanei; Masumi Tsuda; Tomomi Nemoto; Jian Ping Gong; Shinya Tanaka
  Scientific Reports, 13, 1, Feb. 2023
  Scientific journal
• ERK MAP Kinase Signaling Regulates RAR Signaling to Confer Retinoid Resistance on Breast Cancer Cells
  Akira Hirota; Jean-Emmanuel Clément; Satoshi Tanikawa; Takayuki Nonoyama; Tamiki Komatsuzaki; Jian Ping Gong; Shinya Tanaka; Masamichi Imajo
  Cancers, 14, 23, 5890, 5890, MDPI AG, 29 Nov. 2022, [Peer-reviewed]
  English, Scientific journal, Retinoic acid (RA) and its synthetic derivatives, retinoids, have been established as promising anticancer agents based on their ability to regulate cell proliferation and survival. Clinical trials, however, have revealed that cancer cells often acquire resistance to retinoid therapy. Therefore, elucidation of underlying mechanisms of retinoid resistance has been considered key to developing more effective use of retinoids in cancer treatment. In this study, we show that constitutive activation of ERK MAP kinase signaling, which is often caused by oncogenic mutations in RAS or RAF genes, suppresses RA receptor (RAR) signaling in breast cancer cells. We show that activation of the ERK pathway suppresses, whereas its inhibition promotes, RA-induced transcriptional activation of RAR and the resultant upregulation of RAR-target genes in breast cancer cells. Importantly, ERK inhibition potentiates the tumor-suppressive activity of RA in breast cancer cells. Moreover, we also reveal that suppression of RAR signaling and activation of ERK signaling are associated with poor prognoses in breast cancer patients and represent hallmarks of specific subtypes of breast cancers, such as basal-like, HER2-enriched and luminal B. These results indicate that ERK-dependent suppression of RAR activity underlies retinoid resistance and is associated with cancer subtypes and patient prognosis in breast cancers.
• Biomaterials for intestinal organoid technology and personalized disease modeling
  Akira Hirota; Shaikha AlMusawi; Abdolrahman S. Nateri; Paloma Ordóñez-Morán; Masamichi Imajo
  Acta Biomaterialia, Elsevier {BV}, Sep. 2021, [Peer-reviewed], [Last author, Corresponding author]
  English, Scientific journal
• 転写因子Pdx1は小腸内のGIP遺伝子を制御して加齢に伴うGIP分泌亢進に関与する
  池口 絵理; 原田 範雄; 金丸 良徳; 三小田 亜希子; 山根 俊介; 岩崎 可南子; 今城 正道; 村田 由貴; 鈴木 和代; 城尾 恵里奈; 稲垣 暢也
  日本内分泌学会雑誌, 95, 1, 471, 471, (一社)日本内分泌学会, Apr. 2019
  Japanese
• Divergent Dynamics and Functions of ERK MAP Kinase Signaling in Development, Homeostasis and Cancer: Lessons from Fluorescent Bioimaging
  Yu Muta; Michiyuki Matsuda; Masamichi Imajo; corresponding author
  Cancers, 11, 4, 513, Apr. 2019, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
  English, Scientific journal, The extracellular signal-regulated kinase (ERK) signaling pathway regulates a variety of biological processes including cell proliferation, survival, and differentiation. Since ERK activation promotes proliferation of many types of cells, its deregulated/constitutive activation is among general mechanisms for cancer. Recent advances in bioimaging techniques have enabled to visualize ERK activity in real-time at the single-cell level. Emerging evidence from such approaches suggests unexpectedly complex spatiotemporal dynamics of ERK activity in living cells and animals and their crucial roles in determining cellular responses. In this review, we discuss how ERK activity dynamics are regulated and how they affect biological processes including cell fate decisions, cell migration, embryonic development, tissue homeostasis, and tumorigenesis.
• Dynamic ERK signaling regulation in intestinal tumorigenesis
  Yu Muta; Michiyuki Matsuda; Masamichi Imajo; corresponding author
  Molecular & Cellular Oncology, 5, 5, e1506684, Informa {UK} Limited, Sep. 2018, [Peer-reviewed], [Last author, Corresponding author], [International Magazine]
  English, Scientific journal, Extracellular signal-regulated kinase (ERK) plays a critical role in tissue homeostasis and tumorigenesis. By utilizing live imaging approaches, we recently uncovered ERK activity dynamics in the intestinal epithelium. Notably, we showed that ERK activity dynamics are defined by composite regulation from two distinct upstream receptors, and alteration of their functional balance underlies tumor cell-specific traits. Here, we discuss these findings.
• Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice
  Eri Ikeguchi; Norio Harada; Yoshinori Kanemaru; Akiko Sankoda; Shunsuke Yamane; Kanako Iwasaki; Masamichi Imajo; Yuki Murata; Kazuyo Suzuki; Erina Joo; Nobuya Inagaki
  American Journal of Physiology - Gastrointestinal and Liver Physiology, 315, 2, G272, G282, 09 Aug. 2018, [Peer-reviewed]
  English, Scientific journal
• Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine
  Yu Muta; Yoshihisa Fujita; Kenta Sumiyama; Atsuro Sakurai; Makoto M. Taketo; Tsutomu Chiba; Hiroshi Seno; Kazuhiro Aoki; Michiyuki Matsuda; Masamichi Imajo; corresponding author
  Nature Communications, 9, 1, 2174, 2174, Jun. 2018, [Peer-reviewed], [Last author, Corresponding author]
  English, Scientific journal
• 転写因子Pdx1は小腸内のGIP遺伝子を正に制御して加齢に伴うGIP分泌亢進に関与する
  池口 絵理; 原田 範雄; 金丸 良徳; 三小田 亜希子; 山根 俊介; 岩崎 可南子; 今城 正道; 村田 由貴; 鈴木 和代; 城尾 恵里奈; 稲垣 暢也
  糖尿病, 61, Suppl.1, S, 134, (一社)日本糖尿病学会, Apr. 2018
  Japanese
• A Highly Sensitive FRET Biosensor for AMPK Exhibits Heterogeneous AMPK Responses among Cells and Organs
  Yumi Konagaya; Kenta Terai; Yusuke Hirao; Kanako Takakura; Masamichi Imajo; Yuji Kamioka; Norio Sasaoka; Akira Kakizuka; Kenta Sumiyama; Tomoichiro Asano; Michiyuki Matsuda
  CELL REPORTS, 21, 9, 2628, 2638, Nov. 2017, [Peer-reviewed]
  English, Scientific journal
• Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells
  Masamichi Imajo; Kunio Kondoh; Takuya Yamamoto; Kei Nakayama; May Nakajima-Koyama; Eisuke Nishida; corresponding author
  Molecular and Cellular Biology, 37, 15, e00012-17, Jul. 2017, [Peer-reviewed], [Lead author, Corresponding author]
  English, Scientific journal
• Live imaging of extracellular signal-regulated kinase and protein kinase A activities during thrombus formation in mice expressing biosensors based on Forster resonance energy transfer
  T. Hiratsuka; T. Sano; H. Kato; N. Komatsu; M. Imajo; Y. Kamioka; K. Sumiyama; F. Banno; T. Miyata; M. Matsuda
  JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 15, 7, 1487, 1499, Jul. 2017, [Peer-reviewed]
  English, Scientific journal
• Cell competition with normal epithelial cells promotes apical extrusion of transformed cells through metabolic changes
  Shunsuke Kon; Kojiro Ishibashi; Hiroto Katoh; Sho Kitamoto; Takanobu Shirai; Shinya Tanaka; Mihoko Kajita; Susumu Ishikawa; Hajime Yamauchi; Yuta Yako; Tomoko Kamasaki; Tomohiro Matsumoto; Hirotaka Watanabe; Riku Egami; Ayana Sasaki; Atsuko Nishikawa; Ikumi Kameda; Takeshi Maruyama; Rika Narumi; Tomoko Morita; Yoshiteru Sasaki; Ryosuke Enoki; Sato Honma; Hiromi Imamura; Masanobu Oshima; Tomoyoshi Soga; Jun-ichi Miyazaki; Michael R. Duchen; Jin-Min Nam; Yasuhito Onodera; Shingo Yoshioka; Junichi Kikuta; Masaru Ishii; Masamichi Imajo; Eisuke Nishida; Yoichiro Fujioka; Yusuke Ohba; Toshiro Sato; Yasuyuki Fujita
  NATURE CELL BIOLOGY, 19, 5, 530, +, May 2017, [Peer-reviewed]
  English, Scientific journal
• Identification of Aging-Associated Gene Expression Signatures That Precede Intestinal Tumorigenesis
  Yoshihisa Okuchi; Masamichi Imajo; Rei Mizuno; Yuji Kamioka; Hiroyuki Miyoshi; Makoto Mark Taketo; Satoshi Nagayama; Yoshiharu Sakai; Michiyuki Matsuda
  PLOS ONE, 11, 9, Sep. 2016, [Peer-reviewed]
  English, Scientific journal
• HOXA5 Counteracts Stem Cell Traits by Inhibiting Wnt Signaling in Colorectal Cancer
  Paloma Ordonez-Moran; Caroline Dafflon; Masamichi Imajo; Eisuke Nishida; Joerg Huelsken
  CANCER CELL, 28, 6, 815, 829, Dec. 2015, [Peer-reviewed]
  English, Scientific journal
• Dual role of YAP and TAZ in renewal of the intestinal epithelium
  Masamichi Imajo; Miki Ebisuya; Eisuke Nishida
  NATURE CELL BIOLOGY, 17, 1, 7, +, Jan. 2015, [Peer-reviewed], [Lead author, Corresponding author]
  English, Scientific journal
• HVJ-E-mediated gene transfer into the intestinal epithelium
  M. Imajo; M. Ebisuya; E. Nishida
  Protocol Exchange, doi: 10.1038/protex.2014.049, Dec. 2014
  English, Scientific journal
• In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines
  Rei Mizuno; Yuji Kamioka; Kenji Kabashima; Masamichi Imajo; Kenta Sumiyama; Eiji Nakasho; Takeshi Ito; Yoko Hamazaki; Yoshihisa Okuchi; Yoshiharu Sakai; Etsuko Kiyokawa; Michiyuki Matsuda
  JOURNAL OF EXPERIMENTAL MEDICINE, 211, 6, 1123, 1136, Jun. 2014, [Peer-reviewed]
  English, Scientific journal
• A molecular mechanism that links Hippo signalling to the inhibition of Wnt/beta-catenin signalling
  Masamichi Imajo; Koichi Miyatake; Akira Iimura; Atsumu Miyamoto; Eisuke Nishida
  EMBO JOURNAL, 31, 5, 1109, 1122, Mar. 2012, [Peer-reviewed], [Lead author]
  English, Scientific journal
• Human Tribbles homolog 1 functions as a negative regulator of retinoic acid receptor
  Masamichi Imajo; Eisuke Nishida
  GENES TO CELLS, 15, 10, 1089, 1097, Oct. 2010, [Peer-reviewed]
  English, Scientific journal
• Regulatory mechanisms and functions of MAP kinase signaling pathways
  M Imajo; Y Tsuchiya; E Nishida
  IUBMB LIFE, 58, 5-6, 312, 317, May 2006, [Peer-reviewed]
  English, Scientific journal

• Analysis of molecular mechanisms underlying colon cancer development by 3D culture system
  Atsuro Sakurai; Masamichi Imajo; Michiyuki Matsuda, CANCER RESEARCH, 73, Oct. 2013
  English, Summary international conference

• Experimental Medicine Vol.33 No.18 (November) 2015
  Masamichi Imajo; Eisuke Nishida, Role of Hippo signaling in controlling intestinal homeostasis
  Yodosha CO., LTD., Nov. 2015, [Contributor]
• 「生体の科学」66巻5号
  今城 正道, 26. Wntシグナル
  公益財団法人金原一郎記念医学医療振興財団「生体の科学」編集室, 2015, [Contributor]

• Analysis of molecular mechanisms underlying development of hepatoblastoma by using a novel organoid culture system
  Masamichi Imajo; Michiyuki Matsuda
  The 68th Annual Meeting of the Japan Society for Cell Biology, Jun. 2016, Japanese
• Role of the Hippo pathsay in stem cell-driven renewal of the intestinal epithelium
  Masamichi Imajo; Eisuke Nishida
  Biochemistry and Molecular Biology (BMB) 2015, 03 Dec. 2015, Japanese, Invited oral presentation
  [Invited], [Domestic Conference]
• 組織幹細胞の制御におけるHippo経路の新たな役割
  今城 正道
  第8回Symphony, 26 Sep. 2015, Japanese, Invited oral presentation
  [Invited], [Domestic Conference]
• Novel regulatory mechanisms of intestinal stem cell function revealed by in vivo gene transfer
  Masamichi Imajo
  The 66th Annual Meeting of the Japanese Society for Cell Biology, 13 Jun. 2014, The Japanese Society for Cell Biology, English, Invited oral presentation
  奈良県新公会堂, [Invited], [Domestic Conference]
• Analysis on the signal transduction network controlling intestinal homeostasis
  Masamichi Imajo; Eisuke Nishida
  The 84th Annual Meeting of the Japanese Biochemical Society, 23 Sep. 2011, 日本生化学会, Japanese, Invited oral presentation
  [Invited], [Domestic Conference]

• ソフトマター医工学特論, 2024年, 修士課程, 生命科学院

• 腸上皮幹細胞の胎児化による大腸癌発生機構の解明
  科学研究費助成事業
  01 Apr. 2022 - 31 Mar. 2025
  今城 正道
  日本学術振興会, 基盤研究(C), 北海道大学, 22K06874
• Elucidation of molecular mechanisms underlying intestinal stem cell responses to environmental stimuli and their physiological significance
  Grants-in-Aid for Scientific Research
  01 Apr. 2018 - 31 Mar. 2021
  Imajo Masamichi
  Functions of intestinal stem cells (ISCs) are modulated in response to environmental perturbations to maintain tissue homeostasis. In this study, we showed that changes in ERK MAP kinase activity dynamics regulate ISC responses to environmental stimuli. After infection with certain pathogens, Notch signaling inhibition promotes differentiation of ISCs into secretory lineages. We found that Notch signaling inhibition promotes pulse-like activation of ERK and induces expression of Atoh1, a master regulator of secretory differentiation, thereby promoting the differentiation. In addition, we also showed that ERK activity dynamics are changed during intestinal tumorigenesis, which underlies tumor-specific dependency on EGFR signaling. Our results indicate that ERK activity dynamics are dramatically changed depending on the intrinsic tissue status and the environmental stimuli, which plays a critical role in controlling ISC functions in both normal homeostasis and tumorigenesis.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), 18K06929
• 細胞ダイバーシティーを基盤とした腸上皮組織の恒常性維持機構の解明
  科学研究費助成事業
  01 Apr. 2018 - 31 Mar. 2020
  今城 正道
  本研究では、哺乳類腸上皮において細胞社会のダイバーシティーが組織の環境応答や恒常性に果たす役割を明らかにし、その異常と腸疾患との関わりを理解することを目指した。この目標を達成するために、病態モデルマウスや腸上皮オルガノイド、生体イメージング技術を駆使した研究を行い、特にEGFR-ERK MAPキナーゼ経路が細胞ダイバーシティーの制御に重要な役割を果たすことを見出した。
  ERKは細胞増殖の制御に重要な役割を果たすことが知られているが、実際の生体内でいつ、どのように活性化するのかは未解明の部分が多い。そこで本研究では先ず、最新の生体イメージング技術を駆使し、生きたマウス腸上皮におけるERK活性の動態を単一細胞レベルで測定した。その結果、腸上皮ではERK活性には一定の基底状活性と一過的なパルス状活性の二つの成分があることが分かった。このうち、基底状活性はErbB2受容体が、一方パルス状活性はEGFRが駆動していた。さらに、腸上皮腫瘍の形成過程では、EGFR制御因子の発現変化によりEGFRシグナルが増強され、パルス状活性の頻度が上昇すること、同時に基底状活性もEGFR依存性に変化することが示された。この結果は、腫瘍細胞の高いEGFR依存性を説明するものであり、ERK活性の動態の変化が腫瘍に特異的な性質を賦与すると考えられる。
  腫瘍形成に加えて、EGFR-ERK経路の動態の変化は幹細胞の分化方向の制御にも重要であった。腸上皮ではある種の病原体の感染に際して、分泌系細胞への分化が促進されることで、細胞のダイバーシティーが変化する。この分化の際に、ERKのパルス状活性化の頻度が上昇すること、それによりAtoh1の発現が誘導されることで、分化が促進されることが分かった。従って、腸上皮ではERK活性の動態が組織の状態に応じて様々に変化し、そのことが細胞の増殖と分化、ひいては細胞社会のダイバーシティーの制御に重要であると考えられる。
  日本学術振興会, 新学術領域研究(研究領域提案型), 18H05100
• Analysis on molecular mechanisms regulating fetal liver stem cells, hepatoblasts, by using a novel organoid culture system
  Grants-in-Aid for Scientific Research
  01 Apr. 2016 - 31 Mar. 2018
  Imajo Masamichi
  In this study, we aimed to reveal mechanisms regulating fetal liver stem cells, hepatoblasts, and also to understand how disturbance of such mechanisms leads to the childhood liver cancer, hepatoblastoma. By using a newly developed in vitro culture method of hepatoblasts, we found that activation of the Hippo pathway effector, YAP, confers long-term self-renewal ability on hepatoblasts, while activation of beta-catenin promotes Wnt signaling-independent growth of hepatoblasts. Activation of both YAP and beta-catenin induced expression of IGF-1, thereby promoting growth factor-independent survival and proliferation of hepatoblasts. Moreover, transplantation of cultured and genetically modified hepatoblasts showed that simultaneous activation of YAP, beta-catenin, and c-Myc induces formation of hepatoblastoma-like tumors in immunodeficient mice. These results identify novel mechanisms regulating hepatoblast cell fate and suggest that disturbance of the mechanisms leads to hepatoblastoma.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Kyoto University, 16K21106
• Regulatory mechanisms and physiological significance of stem cell migration in the adult tissues
  Grants-in-Aid for Scientific Research
  01 Apr. 2013 - 31 Mar. 2016
  IMAJO Masamichi
  Tissue-resident stem cells are located in the specific microenvironment (niche) that supports maintenance and proliferation of these cells. In the intestinal epithelium, Paneth cells reside adjacent to intestinal stem cells, and secrete signaling molecules that promote survival and proliferation of the stem cells. To receive a sufficient amount of these molecules, intestinal stem cells migrate vigorously and form a mosaic pattern with Paneth cells. In this study, we have identified one of molecular mechanisms that regulate the migration of intestinal stem cells and have shown that the YAP-TEAD protein complex plays an important role in regulating this process. These results challenge the current view that stem cells reside statically in their niche environment and suggest that regulation of the stem cell migration should be crucial for the maintenance of tissue homeostasis.
  Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (B), Kyoto University, 25870363