2025/03/13 更新

写真a

モリ ユウタロウ
森 裕太郎
MORI Yutaro
所属
医歯学総合病院 産科婦人科 助教
職名
助教
外部リンク

学位

  • 博士(医学) ( 2020年3月   新潟大学 )

研究キーワード

  • 卵巣癌

  • 三次元培養

  • 子宮体癌

  • シングルセルRNAシークエンス

  • 子宮内膜

  • 不妊症

研究分野

  • ライフサイエンス / 分子生物学  / 婦人科悪性腫瘍

経歴(researchmap)

  • 新潟大学医歯学総合病院   産婦人科   助教

    2023年4月 - 現在

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  • 帝京大学先端総合研究機構

    2022年4月 - 2023年3月

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  • 国立がん研究センター研究所   がん分化制御解析分野

    2020年4月 - 2022年3月

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経歴

  • 新潟大学   医歯学総合病院 産科婦人科   助教

    2023年4月 - 現在

  • 新潟大学   医歯学総合病院 産科婦人科   特任助教

    2018年4月 - 2019年3月

学歴

  • 新潟大学   大学院医歯学総合研究科

    2015年3月 - 2020年3月

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所属学協会

  • 日本生殖医学会

    2017年4月

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  • 日本癌学会

    2016年10月

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  • 日本婦人科腫瘍学会

    2012年8月

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  • 日本産科婦人科学会

    2012年4月

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論文

  • Glycolysis-mTORC1 crosstalk drives proliferation of patient-derived endometrial cancer spheroid cells with ALDH activity. 国際誌

    Haruka Ueda, Tatsuya Ishiguro, Yutaro Mori, Kaoru Yamawaki, Koji Okamoto, Takayuki Enomoto, Kosuke Yoshihara

    Cell death discovery   10 ( 1 )   435 - 435   2024年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer stem cells are associated with aggressive phenotypes of malignant tumors. A prominent feature of uterine endometrial cancer is the activation of the PI3K-Akt-mTOR pathway. In this study, we present variations in sensitivities to a PI3K-Akt-mTORC1 inhibitor among in vitro endometrial cancer stem cell-enriched spheroid cells from clinical specimens. The in vitro sensitivity was consistent with the effects observed in in vivo spheroid-derived xenograft tumor models. Our findings revealed a complementary suppressive effect on endometrial cancer spheroid cell growth with the combined use of aldehyde dehydrogenase (ALDH) and PI3K-Akt inhibitors. In the PI3K-Akt-mTORC1 signaling cascade, the influence of ALDH on mTORC1 was partially channeled through retinoic acid-induced lactate dehydrogenase A (LDHA) activation. LDHA inhibition was found to reduce endometrial cancer cell growth, aligning with the effects of mTORC1 inhibition. Building upon our previous findings highlighting ALDH-driven glycolysis through GLUT1 in uterine endometrial cancer spheroid cells, curbing mTORC1 enhanced glucose transport via GLUT1 activation. Notably, elevated LDHA expression correlated with adverse clinical survival and escalated tumor grade, especially in advanced stages. Collectively, our findings emphasize the pivotal role of ALDH-LDHA-mTORC1 cascade in the proliferation of endometrial cancer. Targeting the interaction between mTORC1 and ALDH-influenced glycolysis holds promise for developing novel strategies to combat this aggressive cancer.

    DOI: 10.1038/s41420-024-02204-y

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  • Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer. 国際誌

    Yutaro Mori, Yoshie Okimoto, Hiroaki Sakai, Yusuke Kanda, Hirokazu Ohata, Daisuke Shiokawa, Mikiko Suzuki, Hiroshi Yoshida, Haruka Ueda, Tomoyuki Sekizuka, Ryo Tamura, Kaoru Yamawaki, Tatsuya Ishiguro, Raul Nicolas Mateos, Yuichi Shiraishi, Yasushi Yatabe, Akinobu Hamada, Kosuke Yoshihara, Takayuki Enomoto, Koji Okamoto

    Cell reports. Medicine   5 ( 5 )   101532 - 101532   2024年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

    DOI: 10.1016/j.xcrm.2024.101532

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  • Anomalous Epithelial Variations and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease. 国際誌

    Naoaki Watanabe, Yu Fujita, Jun Nakayama, Yutaro Mori, Tsukasa Kadota, Yusuke Hayashi, Iwao Shimomura, Takashi Ohtsuka, Koji Okamoto, Jun Araya, Kazuyoshi Kuwano, Yusuke Yamamoto

    American journal of respiratory cell and molecular biology   67 ( 6 )   708 - 719   2022年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown because of the complexity of lung parenchymal and mesenchymal architecture. To identify cell type-specific mechanisms and cell-cell interactions among the multiple lung resident cell types and inflammatory cells that contribute to COPD progression, we profiled 57,918 cells from lungs of patients with COPD, smokers without COPD, and never-smokers using single-cell RNA sequencing technology. We predicted pseudotime of cell differentiation and cell-to-cell interaction networks in COPD. Although epithelial components in never-smokers were relatively uniform, smoker groups represent extensive heterogeneity in epithelial cells, particularly in alveolar type 2 (AT2) clusters. Among AT2 cells, which are generally regarded as alveolar progenitors, we identified a unique subset that increased in patients with COPD and specifically expressed a series of chemokines including CXCL1 and CXCL8. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred significantly increased intercellular networks of inflammatory AT2 cells. Our results identify previously unidentified cell subsets and provide an insight into the biological and clinical characteristics of COPD pathogenesis.

    DOI: 10.1165/rcmb.2021-0555OC

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  • Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium. 国際誌

    Manako Yamaguchi, Hirofumi Nakaoka, Kazuaki Suda, Kosuke Yoshihara, Tatsuya Ishiguro, Nozomi Yachida, Kyota Saito, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Sundaramoorthy Revathidevi, Teiichi Motoyama, Kazuki Tainaka, Roel G W Verhaak, Ituro Inoue, Takayuki Enomoto

    Nature communications   13 ( 1 )   943 - 943   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple vertical glands rise from the basal gland, originate from the same ancestral clone. Moreover, mutant clones detected in the vertical glands diversify by acquiring additional mutations. These results suggest that clonal expansions through the rhizome structures are involved in the mechanism by which mutant clones extend their territories. Furthermore, we show clonal expansions and copy neutral loss-of-heterozygosity events occur early in life, suggesting such events can be tolerated many years in the normal endometrium. Our results of the evolutionary dynamics of mutant clones in the human endometrium will lead to a better understanding of the mechanisms of endometrial regeneration during the menstrual cycle and the development of therapies for the prevention and treatment of endometrium-related diseases.

    DOI: 10.1038/s41467-022-28568-2

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  • NF-κB suppression synergizes with E7386, an inhibitor of CBP/β-catenin interaction, to block proliferation of patient-derived colon cancer spheroids. 国際誌

    Yusuke Kanda, Hirokazu Ohata, Toshiaki Miyazaki, Hiroaki Sakai, Yutaro Mori, Daisuke Shiokawa, Akira Yokoi, Takashi Owa, Atsushi Ochiai, Koji Okamoto

    Biochemical and biophysical research communications   586   93 - 99   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Dysregulated activation of the WNT/β-catenin signaling pathway is essential for the initiation and development of various cancers. E7386, a small-molecule compound, attenuates WNT signaling by blocking the interaction between β-catenin and CREB-binding protein (CBP); hence, it is regarded as a therapeutic candidate for cancers with activated WNT signaling. In the present study, we evaluated the biological characteristics associated with E7386 sensitivity by using a panel of patient-derived colon cancer spheroids. An integrative approach that combined E7386 sensitivity and gene expression profiles revealed that the resistance of the cancer spheroids to E7386 was associated with the activation of the NF-κB pathway. NF-κB pathway inhibitors acted synergistically with E7386 to block proliferation and induce cell cycle arrest in E7386-resistant spheroids. These findings suggest a possibility that a combination of E7386 and NF-κB inhibition may effectively block the proliferation of a subset of colon cancer cells.

    DOI: 10.1016/j.bbrc.2021.11.063

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  • Proposing a molecular classification associated with hypercoagulation in ovarian clear cell carcinoma. 国際誌

    Ryo Tamura, Kosuke Yoshihara, Koji Matsuo, Nozomi Yachida, Ai Miyoshi, Kotaro Takahashi, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kazuaki Suda, Tatsuya Ishiguro, Shujiro Okuda, Teiichi Motoyama, Hirofumi Nakaoka, Akira Kikuchi, Yutaka Ueda, Ituro Inoue, Takayuki Enomoto

    Gynecologic oncology   163 ( 2 )   327 - 333   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Although ovarian clear cell carcinoma (CCC) is associated with high incidence of thromboembolism, the clinicopathological and biological significance of hypercoagulable status in CCC remains unclear. MATERIALS AND METHODS: We retrospectively analyzed pretreatment D-dimer levels, thromboembolic status, and clinical outcome of 125 CCCs in the discovery set and 143 CCCs in two other independent validation sets. Next, we performed RNA sequencing of 93 CCCs and compared coagulation-related gene profiles with 2492 pan-cancer data. We investigated differences in molecular characteristics of CCC subclasses based on coagulation status. RESULTS: In the discovery dataset, D-dimer elevation above the normal range was significantly associated with shorter progression-free and overall survival, irrespective to thromboembolic status. Multivariate analysis identified D-dimer elevation and clinical stage as an independent prognostic factors. We confirmed the prognostic significance of D-dimer elevation in the validation sets. Tissue factor and IL6, which are considered key elements of cancer-induced hypercoagulation, were highly expressed in CCC than in other cancers regardless of D-dimer level. Higher activity of various oncogenic pathways was observed in CCC with compared to without D-dimer elevation. Moreover, hierarchical cluster analysis divided 57 CCCs with D-dimer elevation into immunologically hot and cold tumor subtypes. Hot tumors were characterized by enrichment of T-cell inflamed phenotype, inflammation, the epithelial-mesenchymal transition, and high serum levels of CRP, and cold tumors by enrichment of cell cycle and MYC pathways. CONCLUSIONS: CCC represents hypercoagulable disease and elevate D-dimer is a prognostic factor for decreased survival in CCC. D-dimer high CCC has distinct molecular characteristics into the inflammatory-driven pathway (hot tumor) and the immune-suppressive pathway (cold tumor). Treatment implication of our proposed molecular classification merits further investigation.

    DOI: 10.1016/j.ygyno.2021.08.009

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  • Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance. 国際誌

    Kaoru Yamawaki, Yutaro Mori, Hiroaki Sakai, Yusuke Kanda, Daisuke Shiokawa, Haruka Ueda, Tatsuya Ishiguro, Kosuke Yoshihara, Kazunori Nagasaka, Takashi Onda, Tomoyasu Kato, Tadashi Kondo, Takayuki Enomoto, Koji Okamoto

    Cancer letters   521   29 - 38   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.

    DOI: 10.1016/j.canlet.2021.08.018

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  • Biological significance of KRAS mutant allele expression in ovarian endometriosis. 国際誌

    Nozomi Yachida, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Haruka Ueda, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Hiroaki Kase, Teiichi Motoyama, Takayuki Enomoto

    Cancer science   112 ( 5 )   2020 - 2032   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    KRAS is the most frequently mutated in ovarian endometriosis. However, it is unclear whether the KRAS mutant allele's mRNA is expressed and plays a biological role in ovarian endometriosis. Here, we performed mutation-specific RNA in situ hybridization to evaluate mutant allele expression of KRAS p.G12V, the most frequently detected mutation in ovarian endometriosis in our previous study, in formalin-fixed paraffin-embedded tissue (FFPE) samples of ovarian endometriosis, cancer cell lines, and ovarian cancers. First, we verified that mutant or wild-type allele of KRAS were expressed in all 5 cancer cell lines and 9 ovarian cancer cases corresponding to the mutation status. Next, we applied this assay to 26 ovarian endometriosis cases, and observed mutant allele expression of KRAS p.G12V in 10 cases. Mutant or wild-type allele of KRAS were expressed in line with mutation status in 12 available endometriosis cases for which KRAS gene sequence was determined. Comparison of clinical features between ovarian endometriosis with KRAS p.G12V mutant allele expression and with KRAS wild-type showed that KRAS p.G12V mutant allele expression was significantly associated with inflammation in ovarian endometriosis. Finally, we assessed the spatial distribution of KRAS mutant allele expression in 5 endometriosis cases by performing multiregional sampling. Intratumor heterogeneity of KRAS mutant allele expression was observed in two endometriosis cases, whereas the spatial distribution of KRAS p.G12V mutation signals were diffuse and homogenous in ovarian cancer. In conclusion, evaluation of oncogene mutant expression will be useful for clarifying the biological significance of oncogene mutations in benign tumors.

    DOI: 10.1111/cas.14871

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  • Three-dimensional understanding of the morphological complexity of the human uterine endometrium. 国際誌

    Manako Yamaguchi, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Nozomi Yachida, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Teiichi Motoyama, Yu Watanabe, Shujiro Okuda, Kazuki Tainaka, Takayuki Enomoto

    iScience   24 ( 4 )   102258 - 102258   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The fundamental morphology of the endometrial glands is not sufficiently understood by 2D observation because these glands have complicated winding and branching patterns. To construct a large picture of the endometrial gland structure, we performed tissue-clearing-based 3D imaging of human uterine endometrial tissue. Our 3D immunohistochemistry and layer analyses revealed that the endometrial glands form a plexus network in the stratum basalis and expand horizontally along the muscular layer, similar to the rhizome of grass. We then extended our method to assess the 3D morphology of tissue affected by adenomyosis, a representative "endometrium-related disease," and observed its 3D morphological features, including the direct invasion of endometrial glands into the myometrium and an ant colony-like network of ectopic endometrial glands within the myometrium. Thus, further understanding of the morphology of the human endometrium based on 3D analysis will lead to the identification of the pathogenesis of endometrium-related diseases.

    DOI: 10.1016/j.isci.2021.102258

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  • Establishment of in vitro 3D spheroid cell cultivation from human gynecologic cancer tissues. 国際誌

    Haruka Ueda, Yutaro Mori, Kaoru Yamawaki, Tatsuya Ishiguro, Hirokazu Ohata, Ai Sato, Kentaro Sugino, Nozomi Yachida, Manako Yamaguchi, Kazuaki Suda, Ryo Tamura, Kosuke Yoshihara, Koji Okamoto, Takayuki Enomoto

    STAR protocols   2 ( 1 )   100354 - 100354   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Advanced-stage gynecologic cancer remains a life-threatening disease. Here, we present a protocol for establishment of stable in vitro 3D spheroid cells derived from human uterine endometrial and ovarian cancer tissues. The tumor-derived spheroid cells have cancer stem cell-related characteristics, including tumorigenesis, and can be used for biological and biochemical analyses and drug efficacy assays. Because these cells possess the biological characteristics of original human tumors, spheroid cells and spheroid-derived xenografts will have applications in personalized medicine in the future. For complete details on the use and execution of this protocol, please refer to Ishiguro et al. (2016) and Mori et al. (2019).

    DOI: 10.1016/j.xpro.2021.100354

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  • Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-like Cells using the Three-dimensional Co-culture System, NICO-1. 国際誌

    Yuko Miyagawa, Kazunori Nagasaka, Kaoru Yamawaki, Yutaro Mori, Tatsuya Ishiguro, Kei Hashimoto, Ryoko Koike, Siho Fukui, Takeru Sugihara, Takayuki Ichinose, Haruko Hiraike, Koichiro Kido, Koji Okamoto, Takayuki Enomoto, Takuya Ayabe

    Journal of visualized experiments : JoVE   ( 166 )   2020年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer stem cells (CSCs) reside in a supportive niche, constituting a microenvironment comprised of adjacent stromal cells, vessels, and extracellular matrix. The ability of CSCs to participate in the development of endothelium constitutes an important characteristic that directly contributes to the general understanding of the mechanisms of tumorigenesis and tumor metastasis. The purpose of this work is to establish a reproducible methodology to investigate the tumor-initiation capability of ovarian cancer stem cells (OCSCs). Herein, we examined the neovascularization mechanism between endothelial cells and OCSCs along with the morphological changes of endothelial cells using the in vitro co-culture model NICO-1. This protocol allows visualization of the neovascularization step surrounding the OCSCs in a time course manner. The technique can provide insight regarding the angiogenetic properties of OCSCs in tumor metastasis.

    DOI: 10.3791/61751

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  • ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis. 国際誌

    Nozomi Yachida, Kosuke Yoshihara, Kazuaki Suda, Hirofumi Nakaoka, Haruka Ueda, Kentaro Sugino, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Tatsuya Ishiguro, Masanori Isobe, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    Scientific reports   10 ( 1 )   14260 - 14260   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.

    DOI: 10.1038/s41598-020-71273-7

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  • Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients. 国際誌

    Kentaro Sugino, Ryo Tamura, Hirofumi Nakaoka, Nozomi Yachida, Manako Yamaguchi, Yutaro Mori, Kaoru Yamawaki, Kazuaki Suda, Tatsuya Ishiguro, Sosuke Adachi, Masanori Isobe, Masayuki Yamaguchi, Katsunori Kashima, Teiichi Motoyama, Ituro Inoue, Kosuke Yoshihara, Takayuki Enomoto

    Scientific reports   9 ( 1 )   17808 - 17808   2019年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.

    DOI: 10.1038/s41598-019-54116-y

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  • ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer. 査読

    Mori Y, Yamawaki K, Ishiguro T, Yoshihara K, Ueda H, Sato A, Ohata H, Yoshida Y, Minamino T, Okamoto K, Enomoto T

    2019年

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    担当区分:筆頭著者  

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  • Novel MXD4-NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma. 国際誌

    Ryo Tamura, Hirofumi Nakaoka, Kosuke Yoshihara, Yutaro Mori, Nozomi Yachida, Nobumichi Nishikawa, Teiichi Motoyama, Shujiro Okuda, Ituro Inoue, Takayuki Enomoto

    Genes, chromosomes & cancer   57 ( 11 )   557 - 563   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in-frame fusion transcripts: MXD4-NUTM1 and ARL6-POT1. Most NUTM1 exons were retained in the MXD4-NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

    DOI: 10.1002/gcc.22668

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  • Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium. 国際誌

    Kazuaki Suda, Hirofumi Nakaoka, Kosuke Yoshihara, Tatsuya Ishiguro, Ryo Tamura, Yutaro Mori, Kaoru Yamawaki, Sosuke Adachi, Tomoko Takahashi, Hiroaki Kase, Kenichi Tanaka, Tadashi Yamamoto, Teiichi Motoyama, Ituro Inoue, Takayuki Enomoto

    Cell reports   24 ( 7 )   1777 - 1789   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.

    DOI: 10.1016/j.celrep.2018.07.037

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  • Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions. 国際誌

    Ryo Tamura, Kosuke Yoshihara, Tetsuya Saito, Ryosuke Ishimura, Juan Emmanuel Martínez-Ledesma, Hu Xin, Tatsuya Ishiguro, Yutaro Mori, Kaoru Yamawaki, Kazuaki Suda, Seiya Sato, Hiroaki Itamochi, Teiichi Motoyama, Yoichi Aoki, Shujiro Okuda, Cristine R Casingal, Hirofumi Nakaoka, Ituro Inoue, Roel G W Verhaak, Masaaki Komatsu, Takayuki Enomoto

    Oncogenesis   7 ( 1 )   4 - 4   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.

    DOI: 10.1038/s41389-017-0018-2

    PubMed

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  • Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer. 国際誌

    Kaoru Yamawaki, Tatsuya Ishiguro, Yutaro Mori, Kosuke Yoshihara, Kazuaki Suda, Ryo Tamura, Masayuki Yamaguchi, Masayuki Sekine, Katsunori Kashima, Masaya Higuchi, Masahiro Fujii, Koji Okamoto, Takayuki Enomoto

    Cancer science   108 ( 4 )   632 - 640   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sex-determining region Y-box 2 (SOX2) is an essential factor involved in the self-renewal and pluripotency of embryonic stem cells and has functions in cell survival and progression in many types of cancers. Here, we found that several endometrial cancer cell lines expressed SOX2, which was required for cell growth. Additionally, SOX2 overexpression regulated the expression of cyclin-dependent kinase inhibitor 1A (CDKN1A), and SOX2 specifically bound to p21 promoter DNA in endometrial cancer cell lines expressing SOX2. Expressions of SOX2 in endometrial cancer patients were significantly correlated with histological grade and poor prognosis. Moreover, low p21 together with high SOX2 expressions in advanced endometrial cancer patients were associated with the most unfavorable outcomes of patients. These results indicated that simultaneous measurement of SOX2 and p21 expression in endometrial cancer patients may be a useful biomarker for patient prognosis.

    DOI: 10.1111/cas.13196

    PubMed

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▶ 全件表示

書籍等出版物

  • 実験医学別冊 空間オミクス解析スタートアップ実践ガイド 最新機器の特徴と目的に合った選び方、データ解析と応用例を学び、シングルセル解析の一歩その先へ!「空間トランスクリプトーム Visiumによる新鮮凍結/FFPE組織検体の解析」

    森裕太郎, 山本雄介, 吉田康将, 岡本康司

    2022年 

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  • 実験医学増刊 Vol.39 No.12: がん微小環境に1細胞レベルで挑む、「シングルセル解析が明らかにするがん幹細胞の治療抵抗性への関与」

    森裕太郎, 塩川大介, 岡本康司( 担当: 分担執筆)

    2021年 

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講演・口頭発表等

  • シングルセル解析と空間的トランスクリプトームの統合による卵巣明細胞癌の治療抵抗性ニッチの解明

    第81回日本癌学会学術総会  2022年 

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    会議種別:シンポジウム・ワークショップ パネル(公募)  

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受賞

  • 第72回日本産科婦人科学会優秀論文賞

    2019年5月   日本産科婦人科学会  

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共同研究・競争的資金等の研究

  • 凍結組織検体の1細胞核解析による卵巣明細胞がんの治療抵抗性細胞ネットワークの解明

    研究課題/領域番号:20K22826

    2020年9月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:研究活動スタート支援

    提供機関:日本学術振興会

    森 裕太郎

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    配分額:2860000円 ( 直接経費:2200000円 、 間接経費:660000円 )

    がん組織はがん細胞と様々な非がん細胞により構成される複雑な組織であるが、がん細胞と癌関連線維芽細胞等の非がん細胞が形成する共生空間は、治療抵抗性と密接な関係があると考えられる。
    本研究では難治性の卵巣明細胞腺がんの治療抵抗性共生空間の本態を明らかにするため、予後情報が判明した症例の凍結組織を対象として、シングル核RNAシークエンス解析と空間的トランスクリプトームの統合解析を行った。統合解析により、治療抵抗性癌細胞群は癌細胞と癌関連線維芽細胞が混在する領域に存在することが明らかとなった。

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