Updated on 2024/03/25

写真a

 
NISHIMURA Tatsunori
 
Organization
Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division for Advanced Medical Research Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor

Education 1

  1. University of Tsukuba

    - 2011.7

 

Papers 29

  1. Cancer-associated fibroblast-derived granulocyte colony-stimulating factor(GCSF) contributes to breast cancer growth and bone metastasis

    Takeuchi Yasuto, Murayama Takahiko, Nishimura Tatsunori, Kahimura Risa, Yano Masao, Tanabe Masahiko, Ishikawa Satoko, Ota Tetsuo, Tada Kei-ichiro, Ikeda Kazuhiro, Horie Kuniko, Inoue Satoshi, Okamoto Koji, Tojo Arinobu, Gotoh Noriko

    Japan Journal of Molecular Tumor Marker Research   Vol. 39 ( 0 ) page: 28 - 28   2024

     More details

    Language:Japanese   Publisher:Japanese Society for Molecular Tumor Marker Research  

    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   Vol. 133 ( 22 )   2023.11

     More details

    Language:English  

    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   Vol. 133 ( 22 )   2023.11

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 674   page: 183 - 189   2023.9

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 14 ( 1 ) page: 4521   2023.8

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 114   page: 1134 - 1134   2023.2

     More details

  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   Vol. 114   page: 1919 - 1919   2023.2

     More details

  8. 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   Vol. 114   page: 375 - 375   2023.2

     More details

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

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

    CANCER SCIENCE   Vol. 114   page: 1133 - 1133   2023.2

     More details

  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   Vol. 113   page: 1325 - 1325   2022.2

     More details

  11. 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   Vol. 113   page: 1476 - 1476   2022.2

     More details

  12. 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   Vol. 113   page: 994 - 994   2022.2

     More details

  13. 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   Vol. 113   page: 1449 - 1449   2022.2

     More details

  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   Vol. 584   page: 7 - 14   2021.12

     More details

    Language:English   Publisher: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

    Scopus

    PubMed

  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   Vol. 118 ( 43 )   2021.10

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 112 ( 9 ) page: 3810 - 3821   2021.9

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 81 ( 13 )   2021.7

     More details

  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   Vol. 12 ( 4 ) page: 322   2021.3

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 112 ( 3 ) page: 1209 - 1224   2021.3

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 112   page: 702 - 702   2021.2

     More details

  21. 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   Vol. 112   page: 705 - 705   2021.2

     More details

  22. 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   Vol. 112   page: 696 - 696   2021.2

     More details

  23. 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   Vol. 112   page: 697 - 697   2021.2

     More details

  24. 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   Vol. 112   page: 173 - 173   2021.2

     More details

  25. 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   Vol. 112   page: 697 - 697   2021.2

     More details

  26. Cancer treatments targeting mitochondrial enzymes involved in one-carbon metabolism Reviewed

    Nishimura Tatsunori, Jin Lee, Xiaoxi Chen, Tojo Arinobu, Gotoh Noriko

    Cytometry Research   Vol. 30 ( 2 ) page: 9 - 13   2020.12

     More details

    Language:Japanese   Publisher:Japan Cytometry Society  

    <p>One-carbon metabolism, also called folate-mediated metabolism, has been targeted for the treatment of patients with cancer. However, therapeutic windows available to the inhibitors of one-carbon metabolism are limited and some patients have been shown to develop resistance to anti-folate drugs. Recently, we showed that mitochondrial enzymes involved in one-carbon metabolism have greater specifi city toward cancer cells than the cytoplasmic enzymes. In our study, we knocked down the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase (MTHFD2) gene in order to inhibit the activity of one such mitochondrial enzyme. Cell cycle progression was analyzed using propidium iodide, and stem cell-like nature was evaluated in terms of aldehyde dehydrogenase activity on a fl ow cytometric setup. Our results showed a drastic decrease in cellular proliferation and stem cell-like phenotypes in the MTHFD2 knockdown cells. From a mechanistic point of view, the inhibition of cellular growth could be predominantly ascribed to the depletion of purine nucleotides, and that of stem cell-like phenotypes was attributable to the accumulation of 1-(5'-phosphoribosyl)-5-amino-4- imidazolecarboxamide.</p>

    DOI: 10.18947/cytometryresearch.30.2_9

    CiNii Research

  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   Vol. 111 ( 12 ) page: 4359 - 4370   2020.12

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 38 ( 14 ) page: 2464 - 2481   2019.4

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

  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   Vol. 116 ( 2 ) page: 625 - 630   2019.1

     More details

    Language:English   Publisher: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

    Web of Science

    Scopus

    PubMed

▼display all

KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. Identification of mechanisms of metastasis mediated by the inhibiton of mitochondrial enzymes of one-carbon metabolism

    Grant number:23K06610  2023.4 - 2026.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

  2. Analyisis of cancer microenvironment under inhibition of enzymes of mitochondrial one-carbon metabolism

    Grant number:19K16768  2019.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Nishimura Tatsunori

      More details

    We first generated conditional knock-out mice of Mthfd2 at mammary epithelial cells, since whole body knock-out mice are embryonic lethal. To this end, we crossed Mthfd2-flox mice with MMTV-Cre mice, which express Cre protein specifically at mammary epithelial cells. Thereafter, we further crossed this mice with MMTV-neu mice, which are one of the breast cancer mouse model. As we expected, Mthfd2 could not be detected at protein level only at mammary epithelial cells.
    When we analyzed phenotype not relevant to breast cancer, there were no problems on birth, and on breastfeeding. To date, we could not obesrve any changes in Mthfd2 knock-out normal mammary epithelial cells.