分子病態治療研究センター

口丸 高弘

クチマル タカヒロ  (Takahiro Kuchimaru)

基本情報

所属
自治医科大学 分子病態治療研究センター 循環病態・代謝学研究部 教授
学位
博士(工学)(大阪大学)

研究者番号
10570591
J-GLOBAL ID
201601015803169501
researchmap会員ID
7000018052

外部リンク

論文

 63
  • Misa Minegishi, Takahiro Kuchimaru, Kaori Nishikawa, Takayuki Isagawa, Satoshi Iwano, Kei Iida, Hiromasa Hara, Shizuka Miura, Marika Sato, Shigeaki Watanabe, Akifumi Shiomi, Yo Mabuchi, Hiroshi Hamana, Hiroyuki Kishi, Tatsuyuki Sato, Daigo Sawaki, Shigeru Sato, Yutaka Hanazono, Atsushi Suzuki, Takahide Kohro, Tetsuya Kadonosono, Tomomi Shimogori, Atsushi Miyawaki, Norihiko Takeda, Hirofumi Shintaku, Shinae Kizaka-Kondoh, Satoshi Nishimura
    Nature Communications 14(1) 2023年12月5日  
    Abstract Cancer cells inevitably interact with neighboring host tissue-resident cells during the process of metastatic colonization, establishing a metastatic niche to fuel their survival, growth, and invasion. However, the underlying mechanisms in the metastatic niche are yet to be fully elucidated owing to the lack of methodologies for comprehensively studying the mechanisms of cell–cell interactions in the niche. Here, we improve a split green fluorescent protein (GFP)-based genetically encoded system to develop secretory glycosylphosphatidylinositol-anchored reconstitution-activated proteins to highlight intercellular connections (sGRAPHIC) for efficient fluorescent labeling of tissue-resident cells that neighbor on and putatively interact with cancer cells in deep tissues. The sGRAPHIC system enables the isolation of metastatic niche-associated tissue-resident cells for their characterization using a single-cell RNA sequencing platform. We use this sGRAPHIC-leveraged transcriptomic platform to uncover gene expression patterns in metastatic niche-associated hepatocytes in a murine model of liver metastasis. Among the marker genes of metastatic niche-associated hepatocytes, we identify Lgals3, encoding galectin-3, as a potential pro-metastatic factor that accelerates metastatic growth and invasion.
  • Nozomi Nishizawa, Takahiro Kuchimaru
    Diffuse Optical Spectroscopy and Imaging IX 2023年8月9日  
  • Hitomi Miyabara, Ryuichiro Hirano, Shigeaki Watanabe, John Clyde Co Soriano, Hitomi Watanabe, Takahiro Kuchimaru, Nobuo Kitada, Tetsuya Kadonosono, Shojiro A. Maki, Gen Kondoh, Shinae Kizaka‐Kondoh
    Cancer Science 114(10) 3935-3945 2023年7月22日  
    Abstract Tumors contain various stromal cells, such as immune cells, endothelial cells, and fibroblasts, which contribute to the development of a tumor‐specific microenvironment characterized by hypoxia and inflammation, and are associated with malignant progression. In this study, we investigated the activity of intratumoral hypoxia‐inducible factor (HIF), which functions as a master regulator of the cellular response to hypoxia and inflammation. We constructed the HIF activity‐monitoring reporter gene hypoxia‐response element‐Venus‐Akaluc (HVA) that expresses the green fluorescent protein Venus and modified firefly luciferase Akaluc in a HIF activity‐dependent manner, and created transgenic mice harboring HVA transgene (HVA‐Tg). In HVA‐Tg, HIF‐active cells can be visualized using AkaBLI, an ultra‐sensitive in vivo bioluminescence imaging technology that produces an intense near‐infrared light upon reaction of Akaluc with the D‐luciferin analog AkaLumine‐HCl. By orthotopic transplantation of E0771, a mouse triple negative breast cancer cell line without a reporter gene, into HVA‐Tg, we succeeded in noninvasively monitoring bioluminescence signals from HIF‐active stromal cells as early as 8 days after transplantation. The HIF‐active stromal cells initially clustered locally and then spread throughout the tumors with growth. Immunohistochemistry and flow cytometry analyses revealed that CD11b+F4/80+ macrophages were the predominant HIF‐active stromal cells in E0771 tumors. These results indicate that HVA‐Tg is a useful tool for spatiotemporal analysis of HIF‐active tumor stromal cells, facilitating investigation of the roles of HIF‐active tumor stromal cells in tumor growth and malignant progression.
  • Yuki Kimura, Hideyuki Ohzawa, Hideyo Miyato, Yuki Kaneko, Takahiro Kuchimaru, Rei Takahashi, Hironori Yamaguchi, Kentaro Kurashina, Shin Saito, Yoshinori Hosoya, Alan Kawarai Lefor, Naohiro Sata, Joji Kitayama
    Cancer Science 2023年4月3日  
  • Tetsuya Kadonosono, Kotaro Miyamoto, Shiori Sakai, Yoshiyuki Matsuo, Shojiro Kitajima, Qiannan Wang, Minori Endo, Mizuho Niibori, Takahiro Kuchimaru, Tomoyoshi Soga, Kiichi Hirota, Shinae Kizaka-Kondoh
    Scientific Reports 12(1) 2022年12月  
    Abstract Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells.

MISC

 29

共同研究・競争的資金等の研究課題

 10