Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

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  THE JAPANESE CANCER ASSOCIATION

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  THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Tumor biology  

Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR

  Kojiro Ishibashi, Toshiya Ichinose, Riki Kadokawa, Ryo Mizutani, Sadahiro Iwabuchi, Sumihito Togi, Hiroki Ura, Shoichiro Tange, Keiko Shinjo, Jun Nakayama, Shigeki Nanjo, Yo Niida, Yutaka Kondo, Shinichi Hashimoto, Erik Sahai, Seiji Yano, Mitsutoshi Nakada, Eishu Hirata

  Developmental Cell ( Elsevier BV )   2024.02  [Refereed]

  DOI

• MYEOV overexpression induced by demethylation of its promoter contributes to pancreatic cancer progression via activation of the folate cycle/c-Myc/mTORC1 pathway.

  Shoichiro Tange, Tomomi Hirano, Masashi Idogawa, Eishu Hirata, Issei Imoto, Takashi Tokino

  BMC cancer   23 ( 1 ) 85 - 85  2023.01  [International journal]

  　View Summary

  BACKGROUND: While molecular targeted drugs and other therapies are being developed for many tumors, pancreatic cancer is still considered to be the malignant tumor with the worst prognosis. We started this study to identify prognostic genes and therapeutic targets of pancreatic cancer. METHODS: To comprehensively identify prognostic genes in pancreatic cancer, we investigated the correlation between gene expression and cancer-specific prognosis using transcriptome and clinical information datasets from The Cancer Genome Atlas (TCGA). In addition, we examined the effects of the suppression of candidate prognostic genes in pancreatic cancer cell lines. RESULT: We found that patients with high expression levels of MYEOV, a primate-specific gene with unknown function, had significantly shorter disease-specific survival times than those with low expression levels. Cox proportional hazards analysis revealed that high expression of MYEOV was significantly associated with poor survival and was an independent prognostic factor for disease-specific survival in pancreatic cancer patients. Analysis of multiple cancer samples revealed that the MYEOV promoter region is methylated in noncancer tissues but is demethylated in tumors, causing MYEOV overexpression in tumors. Notably, the knockdown of MYEOV suppressed the expression of MTHFD2 and other folate metabolism-related enzyme genes required for the synthesis of amino acids and nucleic acids and also restored the expression of c-Myc and mTORC1 repressors. CONCLUSION: There is a significant correlation between elevated MYEOV expression and poor disease-specific survival in pancreatic cancer patients. MYEOV enhances the activation of several oncogenic pathways, resulting in the induction of pancreatic cancer cell proliferation. Overall, MYEOV acts as an oncogene in pancreatic cancer. Furthermore, MYEOV may be a prognostic biomarker and serve as an 'actionable' therapeutic target for pancreatic cancers.

  DOI PubMed

• Inhibition of EGFR and MEK surmounts entrectinib resistance in a brain metastasis model of NTRK1-rearranged tumor cells.

  Chiaki Suzuki, Akihiro Nishiyama, Sachiko Arai, Shoichiro Tange, Atsushi Tajima, Azusa Tanimoto, Koji Fukuda, Yohei Takumi, Hiroshi Kotani, Shinji Takeuchi, Naohiro Yanagimura, Koushiro Ohtsubo, Norio Yamamoto, Koichi Omori, Seiji Yano

  Cancer science   113 ( 7 ) 2323 - 2335  2022.04  [International journal]

  　View Summary

  Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology-agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1-G595R. Repotrectinib is a second-generation TRK inhibitor, which is active against NTRK1-G595R. However, its efficacy against entrectinib-resistant tumors has not been fully elucidated. In the present study, we established entrectinib-resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1-rearranged KM12SM cells, and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1-G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal-regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.

  DOI PubMed

• Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma

  Hiroki Murai, Takahiro Kodama, Kazuki Maesaka, Shoichiro Tange, Daisuke Motooka, Yutaka Suzuki, Yasuyuki Shigematsu, Kentaro Inamura, Yoshihiro Mise, Akio Saiura, Yoshihiro Ono, Yu Takahashi, Yota Kawasaki, Satoshi Iino, Shogo Kobayashi, Masashi Idogawa, Takashi Tokino, Tomomi Hashidate-Yoshida, Hideo Shindou, Masanori Miyazaki, Yasuharu Imai, Satoshi Tanaka, Eiji Mita, Kazuyoshi Ohkawa, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Hidetoshi Eguchi, Eiichi Morii, Tetsuo Takehara

  Hepatology   77 ( 1 ) 77 - 91  2022

  　View Summary

  Background and Aims: Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. Approaches and Results: We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti–PD-L1 and anti-VEGF antibodies. Conclusions: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.

  DOI PubMed

• Early dynamics of circulating tumor DNA predict chemotherapy responses for patients with esophageal cancer.

  Ryosuke Fujisawa, Takeshi Iwaya, Fumitaka Endo, Masashi Idogawa, Noriyuki Sasaki, Hayato Hiraki, Shoichiro Tange, Tomomi Hirano, Yuka Koizumi, Masakazu Abe, Tomoko Takahashi, Mizunori Yaegashi, Yuji Akiyama, Mari Masuda, Akira Sasaki, Fumiaki Takahashi, Yasushi Sasaki, Takashi Tokino, Satoshi S Nishizuka

  Carcinogenesis   42 ( 10 ) 1239 - 1249  2021.09  [International journal]

  　View Summary

  We investigated whether early circulating tumor DNA (ctDNA) changes, measured using digital PCR (dPCR), can predict later chemotherapy responses in esophageal squamous cell cancer (ESCC). We compared the dynamics of ctDNA and tumor volumes during chemotherapy in 42 ESCC. The accuracy of predictions of later chemotherapy responses were evaluated by the ratio of the variant allele frequency (VAF) of ctDNA (post-/pre-ctDNA) and the total tumor volume (post-/pre-volume) before and after an initial chemotherapy cycle using a receiver-operating characteristic curve analysis. Total positive and negative objective responses (ORs) were defined as either >50% or ≤50% reductions, respectively, in the total tumor volume at the end of first-line chemotherapy. Mutation screening of 43 tumors from 42 patients revealed 96 mutations. The pretreatment dPCR-ctDNA data were informative in 38 patients, using 70 selected mutations (1-3 per patient). The areas under the curve (AUCs) for the post-/pre-volume and post-/pre-ctDNA levels used in predicting the total OR were 0.85 and 0.88, respectively. The optimal cutoff value of post-/pre-ctDNA was 0.13. In 20 patients with post-/pre-volume ≥50%, the total OR could be predicted by the post-/pre-ctDNA with high accuracy; the AUC by post-/pre-ctDNA was higher than that by post-/pre-volume (0.85 vs 0.76, respectively). Patients with low post-/pre-ctDNA (n = 18) had a significantly better overall survival rate than those with high post-/pre-ctDNA (n = 20; P = 0.03). Early ctDNA changes after an initial cycle of chemotherapy predict later responses to treatment with high accuracy in ESCC patients.

  DOI PubMed

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• Molecular mechanisms of suppression of Claudin-1 expression in oral cancer cell lines

  丹下正一朗, 井戸川雅史, 川島秀器, 佐々木泰史, 時野隆至

  日本分子生物学会年会プログラム・要旨集(Web)   46th  2023

  J-GLOBAL

• 膵臓がんにおける新規予後予測遺伝子の機能解析

  丹下 正一朗, 平野 朋美, 井戸川 雅史, 平田 英周, 井本 逸勢, 時野 隆至

  日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [J15 - 6]  2021.09

• 長鎖非コードRNA lncAC1は大腸癌の進行を促進する

  小泉 昌代, 井戸川 雅史, 丹下 正一朗, 時野 隆至

  日本癌学会総会記事 ( (一社)日本癌学会 )  80回   [P14 - 5]  2021.09

• カスタムパネルシーケンスを用いた日本人メラノーマのドライバー遺伝子の検出

  肥田 時征, 井戸川 雅史, 堀本 浩平, 加藤 潤史, 佐藤 さゆり, 藤岡 茉生, 丹下 正一朗, 時野 隆至, 宇原 久

  日本皮膚科学会雑誌 ( (公社)日本皮膚科学会 )  131 ( 5 ) 1363 - 1363  2021.05

• 日本人口腔扁平上皮癌における全exome解析

  佐々木泰史, 中垣貴文, 中垣貴文, 荻和弘, 丹下正一朗, 井戸川雅史, 宮崎晃亘, 時野隆至

  日本分子生物学会年会プログラム・要旨集(Web)   42nd  2019

  J-GLOBAL

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Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• Mechanobiology of metastasis

  Fund for the Promotion of Joint International Research (International Collaborative Research)

  Project Year :

  2023.09

  -

  2027.03

   

  石原 誠一郎, 石井 琢郎, 石橋 公二朗, 丹下 正一朗

• 口腔がん組織において予後マーカーとなりうるPRC2構成蛋白質の機能探索

  基盤研究(C)

  Project Year :

  2020.04

  -

  2023.03

   

  丹下 正一朗

  　View Summary

  PRC2複合体を標的としたsiRNAによるノックダウン実験により、口腔癌細胞株における増殖能力の変化を検討した。一部の細胞株においては、ノックダウンによる増力能力への影響が確認された。また、ノックダウン細胞から抽出したRNAを用いたRNA-Seqを行い、PRC2構成遺伝子がノックダウンされた場合の影響を検討した。

• Functional analysis of the caveola-specific protein during tumor progression

  Grant-in-Aid for Young Scientists (B)

  Project Year :

  2017.04

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  2020.03

   

  Tange Shoichiro

  　View Summary

  In this study, we analyzed the genes identified as candidate prognostic markers across carcinomas. Analysis of TCGA information in a database of clinical specimens showed that some candidate genes were up-regulated in some tumors, including breast cancer, and that the overall survival of the high expression group was significantly shorter than that of the low expression group. Quantitative PCR experiments using a breast cancer cell line cDNA also showed enhanced transcription of the gene. However, we counld not observe the protein translated from the gene. Thus, although this gene does not directly contribute to the malignant transformation of tumors, it is considered to be a valid marker of poor prognosis malignancy because elevated transcriptional levels correlate with shorter survival.

• Platform for Advanced Genome Science

  Grant-in-Aid for Scientific Research on Innovative Areas ― Platforms for Advanced Technologies and Research Resources

  Project Year :

  2016

  -

  2021

   

  KOHARA Yuji, Kato Kazuto, Kawashima Minae, TOYODA Atsushi, Suzuki Yutaka, MITSUI Jun, Hayashi Tetsuya, TOKINO Takashi, Kurokawa Ken, Nakamura Yasukazu, Noguchi Hideki, IWASAKI WATARU, Morishita Shinichi, Asai Kiyoshi, Kasahara Masahiro, Ito Takehiko, Yamada Takuji, KUHARA Satoshi, Takahashi Hiroki, Sakakibara Yasubumi, HAMADA MICHIAKI, Takagi Toshihisa, SESE JUN, Ogura Yoshitoshi, Ida Ryuichi, YAMAGATA Zentaro, Masui Toru, Muto Kaori, Kodama Satoshi, Setoyama Koichi, Kokado Minori, Ohashi Noriko, FUJIYAMA Asao, INOUE Ituro, Nakaoka Hirofumi, Sugano Sumio, Tsuji Shoji, Gotoh Yasuhiro, Nakamura Keiji, Ogura Yoshitoshi, Okuno Miki, Nakase Hiroshi, SASAKI Yasushi, IDOGAWA Masashi, Tange Shoichiro, Mori Hiroshi, OGASAWARA Osamu, Tanizawa Yasuhiro, Kondo Shinji, kiryu hisanori, Kajitani Rei, TASHIRO Kosuke, Frith Martin, HIRAKAWA Hideki, Suzuki Hiromu, NOSHO KATSUHIKO, KAI Masahiro

  　View Summary

  Our group has provided the state of art genome technologies, named PAGS Support, including de novo genome sequencing, variation analysis, epigenomics, RNA analysis, metagenome analysis and single cell analysis, to the projects that were selected from proposals based on KAKENHI projects. Thus far, we have provided PAGS Support to altogether 912 proposals that were selected from 1988 proposals. The proposals cover the most fields of life sciences, expanding to the fields of physical sciences, environmental studies and so on. Thus far 556 papers have been published as the outcome, which covers from biology to agriculture, medicine and pharmacy, from basic to applied sciences. Our group has also developed new technologies and algorithms to overcome the problems emerged in the PAGS Support, which are used in the other PAGS Support projects. This is a positive cycle and therefore our system becomes a very effective way for the promotion of biological sciences.

• An investigation for involvement of TET1 gene in tumorigenesis

  Grant-in-Aid for Young Scientists (B)

  Project Year :

  2014.04

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  2017.03

   

  Tange Shoichiro

  　View Summary

  On the other hand there have been many reports of the relationship between the molecular machinery of DNA methylation and malignant tumor, the relationship of DNA demethylation mechanism and cancer remains unclear. Upon starting the research, we have found that the transcriptional level of TET1 (Ten-eleven translocation 1) gene, a member of active DNA demethylation pathway, is not only upregulated in some cell lines but also downregulated in other cancer cell lines. We found the cellular environment inducing transcriptional repression or upregulation of TET1 gene and the candidate of TET1 target genes.