2024/03/25 更新

写真a

ニシムラ タツノリ
西村 建德
NISHIMURA Tatsunori
所属
大学院医学系研究科 附属医学教育研究支援センター 先端領域支援部門 助教
大学院担当
大学院医学系研究科
学部担当
医学部 医学科
職名
助教

学歴 1

  1. 筑波大学

    - 2011年7月

 

論文 29

  1. がん関連線維芽細胞由来の顆粒球コロニー刺激因子GCSF は、乳がんの増殖と骨転移に寄与する

    竹内 康人, 村山 貴彦, 西村 建徳, 柏村 里沙, 矢野 正雄, 田辺 真彦, 石川 聡子, 太田 哲生, 多田 敬一郎, 池田 和博, 堀江 公仁子, 井上 聡, 岡本 康司, 東條 有伸, 後藤 典子

    日本分子腫瘍マーカー研究会誌   39 巻 ( 0 ) 頁: 28 - 28   2024年

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    記述言語:日本語   出版者・発行元:日本分子腫瘍マーカー研究会  

    DOI: 10.11241/jsmtmr.39.28

    CiNii Research

  2. FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

    Li Mengjiao, Nishimura Tatsunori, Takeuchi Yasuto, Hongu Tsunaki, Wang Yuming, Shiokawa Daisuke, Wang Kang, Hirose Haruka, Sasahara Asako, Yano Masao, Ishikawa Satoko, Inokuchi Masafumi, Ota Tetsuo, Tanabe Masahiko, Tada Kei-ichiro, Akiyama Tetsu, Cheng Xi, Liu Chia-Chi, Yamashita Toshinari, Sugano Sumio, Uchida Yutaro, Chiba Tomoki, Asahara Hiroshi, Nakagawa Masahiro, Sato Shinya, Miyagi Yohei, Shimamura Teppei, Nagai Luis Augusto E., Kanai Akinori, Katoh Manami, Nomura Seitaro, Nakato Ryuichiro, Suzuki Yutaka, Tojo Arinobu, Voon Dominic C., Ogawa Seishi, Okamoto Koji, Foukakis Theodoros, Gotoh Noriko

    Journal of Clinical Investigation   133 巻 ( 22 )   2023年11月

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    記述言語:英語  

    The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na⁺/K⁺ pump. Accordingly, FXYD3⁺ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3⁺ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3⁺ CSCs were sensitive to senolytic Na⁺/K⁺ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3⁺ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na⁺/K⁺ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.

    CiNii Research

  3. FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

    Li, MJ; Nishimura, T; Takeuchi, Y; Hongu, T; Wang, YM; Shiokawa, D; Wang, K; Hirose, H; Sasahara, A; Yano, M; Ishikawa, S; Inokuchi, M; Ota, T; Tanabe, M; Tada, KI; Akiyama, T; Cheng, X; Liu, CC; Yamashita, T; Sugano, S; Uchida, Y; Chiba, T; Asahara, H; Nakagawa, M; Sato, S; Miyagi, Y; Shimamura, T; Nagai, LAE; Kanai, A; Katoh, M; Nomura, S; Nakato, R; Suzuki, Y; Tojo, A; Voon, DC; Ogawa, S; Okamoto, K; Foukakis, T; Gotoh, N

    JOURNAL OF CLINICAL INVESTIGATION   133 巻 ( 22 )   2023年11月

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    記述言語:英語   出版者・発行元:Journal of Clinical Investigation  

    The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain–containing ion transport regulator 3 (FXYD3), a component of the Na+ /K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+ /K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+ /K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.

    DOI: 10.1172/JCI166666

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  4. Mitochondrial one-carbon metabolic enzyme MTHFD2 facilitates mammary gland development during pregnancy

    Wang, YM; Hongu, T; Nishimura, T; Takeuchi, Y; Takano, H; Daikoku, T; Yao, R; Gotoh, N

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   674 巻   頁: 183 - 189   2023年9月

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    記述言語:英語   出版者・発行元:Biochemical and Biophysical Research Communications  

    Mitochondrial one-carbon metabolism is crucial for embryonic development and tumorigenesis, as it supplies one-carbon units necessary for nucleotide synthesis and rapid cell proliferation. However, its contribution to adult tissue homeostasis remains largely unknown. To examine its role in adult tissue homeostasis, we specifically investigated mammary gland development during pregnancy, as it involves heightened cell proliferation. We discovered that MTHFD2, a mitochondrial one-carbon metabolic enzyme, is expressed in both luminal and basal/myoepithelial cell layers, with upregulated expression during pregnancy. Using the mouse mammary tumor virus (MMTV)-Cre recombinase system, we generated mice with a specific mutation of Mthfd2 in mammary epithelial cells. While the mutant mice were capable of properly nurturing their offspring, the pregnancy-induced expansion of mammary glands was significantly delayed. This indicates that MTHFD2 contributes to the rapid development of mammary glands during pregnancy. Our findings shed light on the role of mitochondrial one-carbon metabolism in facilitating rapid cell proliferation, even in the context of the adult tissue homeostasis.

    DOI: 10.1016/j.bbrc.2023.06.074

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  5. TUG1-mediated R-loop resolution at microsatellite loci as a prerequisite for cancer cell proliferation

    Suzuki, MM; Iijima, K; Ogami, K; Shinjo, K; Murofushi, Y; Xie, JQ; Wang, XB; Kitano, Y; Mamiya, A; Kibe, Y; Nishimura, T; Ohka, F; Saito, R; Sato, S; Kobayashi, J; Yao, R; Miyata, K; Kataoka, K; Suzuki, HI; Kondo, Y

    NATURE COMMUNICATIONS   14 巻 ( 1 ) 頁: 4521   2023年8月

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    記述言語:英語   出版者・発行元:Nature Communications  

    Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation are known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. Here, we report taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA), which is highly expressed in many types of cancers, as an important regulator of intrinsic R-loop in cancer cells. Under RS conditions, TUG1 is rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacts with RPA and DHX9, and engages in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 leads to overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a role of TUG1 as molecule important for resolving R-loop accumulation in cancer cells and suggest targeting TUG1 as a potent therapeutic approach for cancer treatment.

    DOI: 10.1038/s41467-023-40243-8

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  6. FXYD3, a subunit of Na<SUP>+</SUP>K<SUP>+</SUP> pump, determines the root of triple-negative breast cancer stem-like cells

    Li, MJ; Nishimura, T; Shiokawa, D; Yano, M; Ishikawa, S; Ohta, T; Tanabe, M; Tada, K; Akiyama, T; Shimamura, T; Sato, S; Miyagi, Y; Suzuki, Y; Okamoto, K; Tojo, A; Gotoh, N

    CANCER SCIENCE   114 巻   頁: 1134 - 1134   2023年2月

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  7. Elucidation of interaction between breast cancer stem-like cells and cancer-associated fibroblasts

    Takeuchi, Y; Murayama, T; Nishimura, T; Kahimura, R; Matsumoto, H; Yano, M; Tanabe, M; Ishikawa, S; Ohta, T; Tada, K; Ikeda, K; Horie, K; Inoue, S; Okamoto, K; Tojo, A; Gotoh, N

    CANCER SCIENCE   114 巻   頁: 1919 - 1919   2023年2月

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  8. FXYD3 positive CSCs may play a key role in radioresistance

    Yamazaki, M; Nishimura, T; Li, MJ; Gotoh, N

    CANCER SCIENCE   114 巻   頁: 1133 - 1133   2023年2月

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  9. One carbon metabolic enzyme MTHFD2 is essential for breast cancer metastasis to lung

    Wang, YM; Nishimura, T; Li, MJ; Yao, R; Gotoh, N

    CANCER SCIENCE   114 巻   頁: 375 - 375   2023年2月

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  10. Single-cell RNAseq identifies subpopulations of drug resistant cancer stem-like cells in patient-derived breast cancer

    Li, MJ; Nishimura, T; Shiokawa, D; Teppei, S; Sasahara, A; Yano, M; Ishikawa, S; Ota, T; Tada, K; Okamoto, K; Tojo, A; Gotoh, N

    CANCER SCIENCE   113 巻   頁: 1325 - 1325   2022年2月

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  11. Application of organoids to breast cancer research

    Shimono, Y; Nishimura, T; Kono, S; Shibuya, N; Hayashi, T; Yanagi, H; Watanabe, T; Maeda, M; Kakeji, Y; Kawada, K; Asai, N; Takao, S; Minami, H; Kijima, Y; Suzuki, M; Gotoh, N

    CANCER SCIENCE   113 巻   頁: 1449 - 1449   2022年2月

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  12. A novel inhibitor of one carbon metabolism with Chk1 inhibitor is a rational combination strategy to treat breast cancer

    Nishimura, T; Lee, J; Chen, XX; Li, MJ; Wang, YM; Ishikawa, S; Tojo, A; Gotoh, N

    CANCER SCIENCE   113 巻   頁: 1476 - 1476   2022年2月

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  13. FRS2b fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis

    Takeuchi, Y; Kimura, N; Murayama, T; Machida, Y; Iejima, D; Nishimura, T; Wang, YM; Yamamoto, M; Itano, N; Inoue, J; Akashi, K; Saya, H; Kuroda, M; Kitabayashi, I; Tojo, A; Gotoh, N

    CANCER SCIENCE   113 巻   頁: 994 - 994   2022年2月

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  14. A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer

    Lee J., Chen X., Wang Y., Nishimura T., Li M., Ishikawa S., Daikoku T., Kawai J., Tojo A., Gotoh N.

    Biochemical and Biophysical Research Communications   584 巻   頁: 7 - 14   2021年12月

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    記述言語:英語   出版者・発行元:Biochemical and Biophysical Research Communications  

    Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer.

    DOI: 10.1016/j.bbrc.2021.11.001

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  15. The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis

    Takeuchi, Y; Kimura, N; Murayama, T; Machida, Y; Iejima, D; Nishimura, T; Terashima, M; Wang, YM; Li, MJ; Sakamoto, R; Yamamoto, M; Itano, N; Inoue, Y; Ito, M; Yoshida, N; Inoue, JI; Akashi, K; Saya, H; Fujita, K; Kuroda, M; Kitabayashi, I; Voon, D; Suzuki, T; Tojo, A; Gotoh, N

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   118 巻 ( 43 )   2021年10月

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    記述言語:英語   出版者・発行元:Proceedings of the National Academy of Sciences of the United States of America  

    Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2β, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β deficiency in mouse mammary tumor virus (MMTV)–ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found that colocalization of FRS2β and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor–κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB–induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β–NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.

    DOI: 10.1073/pnas.2103658118

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  16. MUSASHI-2 confers resistance to third-generation EGFR-tyrosine kinase inhibitor osimertinib in lung adenocarcinoma

    Yiming, R; Takeuchi, Y; Nishimura, T; Li, MJ; Wang, YM; Meguro-Horike, M; Kohno, T; Horike, S; Nakata, A; Gotoh, N

    CANCER SCIENCE   112 巻 ( 9 ) 頁: 3810 - 3821   2021年9月

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    記述言語:英語   出版者・発行元:Cancer Science  

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with non–small-cell lung cancer (NSCLC) harboring EGFR mutations. However, due to acquired resistance to EGFR-TKIs, even patients on third-generation osimertinib have a poor prognosis. Resistance mechanisms are still not fully understood. Here, we demonstrate that the increased expression of MUSASHI-2 (MSI2), an RNA-binding protein, is a novel mechanism for resistance to EGFR-TKIs. We found that after a long-term exposure to gefitinib, the first-generation EGFR-TKI lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to both gefitinib and osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the stemness-related genes highly upregulated in EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including the expression levels of Nanog, a core stemness factor. We demonstrated that knockdown of MSI2 restored sensitivity to osimertinib or gefitinib in EGFR-TKI-resistant cells to levels similar to those of parental cells in vitro. An RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 were bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to osimertinib or gefitinib in parental cells. Finally, MSI2 knockdown greatly increased the sensitivity to osimertinib in vivo. Collectively, our findings provide proof of principle that targeting the MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent the emergence of acquired resistance.

    DOI: 10.1111/cas.15036

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  17. Role of S100A10 in the metastatic colonization of breast cancer stem cells.

    Shimono, Y; Yanagi, H; Watanabe, T; Nishimura, T; Hayashi, T; Okada, S; Suzuki, M; Kawada, K; Minami, H; Gotoh, N

    CANCER RESEARCH   81 巻 ( 13 )   2021年7月

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  18. Cytoplasmic DNA accumulation preferentially triggers cell death of myeloid leukemia cells by interacting with intracellular DNA sensing pathway

    Baba, T; Yoshida, T; Tanabe, Y; Nishimura, T; Morishita, S; Gotoh, N; Hirao, A; Hanayama, R; Mukaida, N

    CELL DEATH & DISEASE   12 巻 ( 4 ) 頁: 322   2021年3月

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    記述言語:英語   出版者・発行元:Cell Death and Disease  

    Accumulating evidence indicates the presence of cytoplasmic DNAs in various types of malignant cells, and its involvement in anti-cancer drug- or radiotherapy-mediated DNA damage response and replication stress. However, the pathophysiological roles of cytoplasmic DNAs in leukemias remain largely unknown. We observed that during hematopoietic stem cell transplantation (HSCT) in mouse myeloid leukemia models, double-stranded (ds)DNAs were constitutively secreted in the form of extracellular vesicles (EVs) from myeloid leukemia cells and were transferred to the donor cells to dampen their hematopoietic capabilities. Subsequent analysis of cytoplasmic DNA dynamics in leukemia cells revealed that autophagy regulated cytoplasmic dsDNA accumulation and subsequent redistribution into EVs. Moreover, accumulated cytoplasmic dsDNAs activated STING pathway, thereby reducing leukemia cell viability through reactive oxygen species (ROS) generation. Pharmaceutical inhibition of autophagosome formation induced cytoplasmic DNA accumulation, eventually triggering cytoplasmic DNA sensing pathways to exert cytotoxicity, preferentially in leukemia cells. Thus, manipulation of cytoplasmic dsDNA dynamics can be a novel and potent therapeutic strategy for myeloid leukemias.

    DOI: 10.1038/s41419-021-03587-x

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  19. MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells

    Murayama, T; Takeuchi, Y; Yamawaki, K; Natsume, T; Li, MJ; Marcela, RCN; Nishimura, T; Kogure, Y; Nakata, A; Tominaga, K; Sasahara, A; Yano, M; Ishikawa, S; Ohta, T; Ikeda, K; Horie-Inoue, K; Inoue, S; Seki, M; Suzuki, Y; Sugano, S; Enomoto, T; Tanabe, M; Tada, K; Kanemaki, MT; Okamoto, K; Tojo, A; Gotoh, N

    CANCER SCIENCE   112 巻 ( 3 ) 頁: 1209 - 1224   2021年3月

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    記述言語:英語   出版者・発行元:Cancer Science  

    Cancer stem-like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c-Myc. c-Myc-dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient-derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S-phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c-Myc-MCM10 axis for preventing drug resistance and recurrence of tumors.

    DOI: 10.1111/cas.14776

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  20. Cancer associated fibroblast-derived soluble factors contribute to the maintenance of breast cancer stem-like cells

    Takeuchi, Y; Murayama, T; Nishimura, T; Yano, M; Sasahara, A; Tanabe, M; Ishikawa, S; Ota, T; Tada, K; Ikeda, K; Inoue, S; Horie, K; Okamoto, K; Tojo, A; Gotoh, N

    CANCER SCIENCE   112 巻   頁: 702 - 702   2021年2月

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  21. Cancer Stem-like traits are up-regulated in gefitinib-resistant lung cancer cells

    Reheman, Y; Takeuchi, Y; Nishimura, T; Nakata, A; Gotoh, N

    CANCER SCIENCE   112 巻   頁: 697 - 697   2021年2月

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  22. Identification of subpopulations in patient-derived breast cancer stem-like cells by using RNA sequencing

    Nishimura, T; Li, MJ; Shiokawa, D; Shimamura, T; Sasahara, A; Yano, M; Ishikawa, S; Ohta, T; Tada, K; Seong-Jin, K; Okamoto, K; Tojo, A; Gotoh, N

    CANCER SCIENCE   112 巻   頁: 173 - 173   2021年2月

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  23. Upregulation of S100A10 in metastasized breast cancer stem cells.

    Yanagi, H; Watanabe, T; Nishimura, T; Hayashi, T; Okada, S; Suzuki, M; Minami, H; Suzuki, A; Kawada, K; Gotoh, N; Shimono, Y

    CANCER SCIENCE   112 巻   頁: 705 - 705   2021年2月

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  24. Single cell analysis revealed heterogeneity among patient-derived breast cancer stem-like cells

    Li, MJ; Nishimura, T; Sasahara, A; Yano, M; Ishikawa, S; Ohta, T; Tada, K; Shiokawa, D; Okamoto, K; Gotoh, N

    CANCER SCIENCE   112 巻   頁: 696 - 696   2021年2月

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  25. One carbon metabolic enzyme MTHFD1L could be a novel molecular target for breast cancer

    Lee, J; Nishimura, T; Ishikawa, S; Ohta, T; Tojo, A; Gotoh, N

    CANCER SCIENCE   112 巻   頁: 697 - 697   2021年2月

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  26. ミトコンドリア内葉酸代謝酵素を標的としたがん治療 査読有り

    西村 建徳, 東條 有伸, 後藤 典子

    サイトメトリーリサーチ   30 巻 ( 2 ) 頁: 9 - 13   2020年12月

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    記述言語:日本語   出版者・発行元:日本サイトメトリー学会  

    DOI: 10.18947/cytometryresearch.30.2_9

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  27. Upregulation of S100A10 in metastasized breast cancer stem cells

    Yanagi, H; Watanabe, T; Nishimura, T; Hayashi, T; Kono, S; Tsuchida, H; Hirata, M; Kijima, Y; Takao, S; Okada, S; Suzuki, M; Imaizumi, K; Kawada, K; Minami, H; Gotoh, N; Shimono, Y

    CANCER SCIENCE   111 巻 ( 12 ) 頁: 4359 - 4370   2020年12月

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    記述言語:英語   出版者・発行元:Cancer Science  

    Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient-derived tumor xenograft (PDX) mouse model in which CSC marker CD44+ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44+ cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell–related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.

    DOI: 10.1111/cas.14659

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  28. Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2

    Nishimura, T; Nakata, A; Chen, XX; Nishi, K; Meguro-Horike, M; Sasaki, S; Kita, K; Horike, S; Saitoh, K; Kato, K; Igarashi, K; Murayama, T; Kohno, S; Takahashi, C; Mukaida, N; Yano, SJ; Soga, T; Tojo, A; Gotoh, N

    ONCOGENE   38 巻 ( 14 ) 頁: 2464 - 2481   2019年4月

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    記述言語:英語   出版者・発行元:Oncogene  

    Tumor recurrence is attributable to cancer stem-like cells (CSCs), the metabolic mechanisms of which currently remain obscure. Here, we uncovered the critical role of folate-mediated one-carbon (1C) metabolism involving mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and its downstream purine synthesis pathway. MTHFD2 knockdown greatly reduced tumorigenesis and stem-like properties, which were associated with purine nucleotide deficiency, and caused marked accumulation of 5-aminoimidazole carboxamide ribonucleotide (AICAR)—the final intermediate of the purine synthesis pathway. Lung cancer cells with acquired resistance to the targeted drug gefitinib, caused by elevated expression of components of the β-catenin pathway, exhibited increased stem-like properties and enhanced expression of MTHFD2. MTHFD2 knockdown or treatment with AICAR reduced the stem-like properties and restored gefitinib sensitivity in these gefitinib-resistant cancer cells. Moreover, overexpression of MTHFD2 in gefitinib-sensitive lung cancer cells conferred resistance to gefitinib. Thus, MTHFD2-mediated mitochondrial 1C metabolism appears critical for cancer stem-like properties and resistance to drugs including gefitinib through consumption of AICAR, leading to depletion of the intracellular pool of AICAR. Because CSCs are dependent on MTHFD2, therapies targeting MTHFD2 may eradicate tumors and prevent recurrence.

    DOI: 10.1038/s41388-018-0589-1

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  29. Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells

    Tominaga, K; Minato, H; Murayama, T; Sasahara, A; Nishimura, T; Kiyokawa, E; Kanauchi, H; Shimizu, S; Sato, A; Nishioka, K; Tsuji, E; Yano, M; Ogawa, T; Ishii, H; Mori, M; Akashi, K; Okamoto, K; Tanabe, M; Tada, K; Tojo, A; Gotoh, N

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   116 巻 ( 2 ) 頁: 625 - 630   2019年1月

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    記述言語:英語   出版者・発行元:Proceedings of the National Academy of Sciences of the United States of America  

    Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

    DOI: 10.1073/pnas.1806851116

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科研費 2

  1. ミトコンドリア内葉酸代謝阻害による転移抑制機構の解明

    研究課題/研究課題番号:23K06610  2023年4月 - 2026年3月

    科学研究費助成事業  基盤研究(C)

    西村 建徳

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    本研究ではなぜミトコンドリア内葉酸代謝阻害により、再発・転移に関与する腫瘍原生能が低下するのかを阻害剤によるエピゲノム変化を解析することで、原因遺伝子の同定とその変化の機序までを明らかにする。複数あるミトコンドリア内葉酸代謝酵素のうち、本研究では、その特異的阻害剤は唯一存在するMethylenetetrahydrofolate dehydrogenase 2 (MTHFD2)をミトコンドリア葉酸代謝阻害の作用点とする。

  2. ミトコンドリア内葉酸代謝酵素を阻害したときのがん微小環境変化の解析

    研究課題/研究課題番号:19K16768  2019年4月 - 2021年3月

    科学研究費助成事業  若手研究

    西村 建徳

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    我々はヒトがん細胞株においてミトコンドリア内葉酸代謝酵素であるMTHFD2をノックダウンし、免疫不全マウスに移植すると、細胞増殖が顕著に遅くなるだけでなく、腫瘍原生能も低下することを明らかにした。しかし、この移植実験系ではがん細胞の微小環境が自然にできる腫瘍組織と大きく異なり、がん細胞と間質細胞の相互作用については十分に評価することができなかった。そこで、本研究では乳がんマウスモデルを用い、自然にできる腫瘍に近い状態においてMTHFD2の機能を阻害した時、がん細胞と間質細胞の相互作用がどうのように変化するのか、そして形成される腫瘍の性質がどのように変化するのか、という二点について明らかにする。
    Mthfd2のノックアウトマウスは胎生致死のため、本研究ではコンディショナルノックアウトマウスを作成することとした。まず、Mthfd2-floxマウスを作成した。そして、このマウスを乳腺特異的にCreを発現するMMTV-Creマウスと掛け合わせ、さらに乳がんのマウスモデルであるMMTV-neuマウスと掛け合わせた。まず、乳腺のおいてMthfd2がノックアウトされているのかを確認した。次に本マウスの表現型について解析を進めた。まず、がんと関係ない表現型について解析を行った。その結果、出産や授乳をはじめとした表現型は乳腺でMthfd2をノックアウトしても特に問題はないようであった。
    本研究では新規抗癌剤のターゲットして申請者が見出したミトコンドリア内葉酸代謝酵素を阻害した時にがんが身を置く環境(がん微小環境)がどのように変化するかについて解析を行った。がんの悪性化にとってがんそのもの悪性化も大きな要素であるが、同時にがん微小環境ががんの変化によってどのように変化するのかも大きな要素である。本研究では免疫細胞を含めたがん微小環境がミトコンドリア内葉酸代謝酵素を阻害したときにどう変化にするのかについて初めてアプローチした。本研究によりミトコンドリア内葉酸代謝酵素の阻害剤を服用したとき、患者がどのように応答するのかについてより患者に近い形で明らかにすることができた。