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  日本癌学会

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  日本分子生物学会

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• ライフサイエンス   腫瘍生物学  

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• 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年02月  [査読有り]

  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年01月  [国際誌]

  　概要を見る

  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年04月  [国際誌]

  　概要を見る

  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年

  　概要を見る

  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年09月  [国際誌]

  　概要を見る

  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 【 表示 ／ 非表示 】

• 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年09月

• 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年09月

• 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年05月

• 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年

  J-GLOBAL

• RNA結合蛋白質TIA1の細胞内機能調節に着目した新規食道癌治療法の開発

  増田 清士, 河本 知大, 濱田 隼一, 庄田 勝俊, 藤田 悠司, 丹下 正一朗, 斎藤 雅子, 井本 逸勢

  生命科学系学会合同年次大会 ( 生命科学系学会合同年次大会運営事務局 )  2017年度   [3P - 0989]  2017年12月

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共同研究・競争的資金等の研究課題 【 表示 ／ 非表示 】

共同研究・競争的資金等の研究課題 【 表示 ／ 非表示 】

• がん転移におけるメカノバイオロジー

  国際共同研究加速基金(海外連携研究)

  研究期間:

  2023年09月

  -

  2027年03月

   

  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)

  研究期間:

  2020年04月

  -

  2023年03月

   

  丹下 正一朗

  　研究概要を見る

  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。

• 腫瘍の悪性進展過程における筋特異的カベオラ蛋白質MURCの機能解析

  若手研究(B)

  研究期間:

  2017年04月

  -

  2020年03月

   

  丹下 正一朗

  　研究概要を見る

  本研究は、癌腫横断的に予後マーカーとなりうる遺伝子の候補として特定した遺伝子の解析を行ったものである。臨床検体のデータベースであるTCGAの情報を解析した結果、本研究の候補遺伝子は、乳癌をはじめ一部の腫瘍において発現が亢進している群の存在が確認され、高発現群の全生存期間は低発現群に対して有意に短いことが示された。乳癌細胞株を用いた実験では、同遺伝子の転写の亢進も確認されたが、蛋白質の翻訳は確認されなかった。このため、この遺伝子は腫瘍の悪性化に直接寄与しているわけではないものの、転写レベルの上昇が生存期間の短縮との相関を示しているために予後不良な悪性腫瘍のマーカーとして有効であると考えられた。

• DNA脱メチル化関連酵素TET1のがん細胞における機能解析

  若手研究(B)

  研究期間:

  2014年04月

  -

  2017年03月

   

  丹下 正一朗

  　研究概要を見る

  細胞のがん化とゲノムDNAのメチル化との関連については膨大な研究の蓄積があるのに対し、がん化とDNAの脱メチル化制御についての研究は未だ十分ではない。申請者はがん培養細胞株において、DNAの能動的な脱メチル化機構の一員であるTET1(Ten-eleven translocation 1)遺伝子の発現レベルの上昇と低下がそれぞれ異なる局面において起こることを見出したことから、同遺伝子の転写制御機序と悪性腫瘍における機能の解析を行うこととした。これにより、TET1遺伝子の転写抑制が起きる培養環境や、同遺伝子の標的遺伝子候補の同定がなされた。