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In vivo comprehensive genome editing analysis to elucidate the mechanisms of cancer refractoriness for development of novel therapies

Research Project

Project/Area Number 22K19554
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Tanaka Shinji  東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30253420)

Co-Investigator(Kenkyū-buntansha) 新部 彩乃 (樺嶋彩乃)  東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20445448)
島田 周  東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20609705)
秋山 好光  東京医科歯科大学, 大学院医歯学総合研究科, 講師 (80262187)
Project Period (FY) 2022-06-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2023: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2022: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Keywordsゲノム編集 / 難治性がん / 転移 / エピゲノム制御 / 細胞外基質 / CAR-T / 樹状細胞 / 免疫疲弊 / 播種転移 / 肝転移 / 免疫逃避 / 腫瘍関連線維芽細胞(CAF) / 膵癌
Outline of Research at the Start

本研究では、膵癌の肝転移、腹膜播種転移能獲得の分子機序を正常免疫下におけるin vivo網羅的ゲノム編集解析によって解明し、新規治療開発を進める。さらに、膵癌特異的なCAR-T治療を確立し、TCRおよびPD-1の多重ゲノム編集を開発して持続性を高めることに成功したが、癌組織内への浸潤は限定的であることを見出した。in vivo網羅的ゲノム編集解析によってCAR-T細胞の癌組織への浸潤能を促進するメカニズムを解明し、新たな免疫治療を開発する。膵癌は典型的な難治性癌であり、in vivoゲノム編集解析に基づく新規転移制御治療および革新的CAR-T細胞治療の開発は、挑戦的研究として最重要課題である。

Outline of Final Research Achievements

Using in vivo comprehensive genome editing analysis of pancreatic cancer lines derived from C57BL/6 mice, we found that a group of genes related to the antigen presentation mechanism and extracellular matrix (ECM) contributed to the acquisition of metastatic potential in the same strain of mice. We found epigenomic regulation of the antigen-presenting machinery, which may be a potential therapeutic target. Furthermore, we found that ECM signaling and ECM enzyme inhibitors activate dendritic cells with T cells, and prolong prognosis with suppression of metastasis.
We performed in vivo comprehensive genome editing analysis to identify immune-related genes in a mouse model of MSLN+ pancreatic cancer and generated a new CAR vector with additional immune activating genes. The analysis of the therapeutic efficacy of New CAR-T cell therapy revealed the importance of dendritic cell activation, and furthermore, the efficacy was enhanced by the combination of immune exhaustion inhibitors.

Academic Significance and Societal Importance of the Research Achievements

近年のゲノム編集技術の開発によって大きな技術革新が生まれており、治療開発への応用が期待されている。申請者は高効率多重ゲノム編集技術を開発し、初代培養細胞およびCAR-T細胞へ同時に複数の遺伝子変異を導入する革新的手法に成功した。本研究では、高効率ゲノム編集技術をin vivo CRISPR/Cas9 sgRNA library導入へ応用し、膵癌細胞の網羅的ゲノム編集解析により転移能獲得機序を解明し、CAR-T細胞の網羅的ゲノム編集解析により膵癌組織への免疫浸潤機序を解明する。免疫応答モデルを用いて癌細胞および免疫細胞の両面から膵癌の難治性機序を明らかにし、新規治療法を開拓する挑戦的課題である。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (41 results)

All 2024 2023 2022 2021 2020 Other

All Int'l Joint Research (9 results) Journal Article (16 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 16 results,  Open Access: 6 results) Presentation (9 results) (of which Int'l Joint Research: 5 results,  Invited: 9 results) Book (1 results) Remarks (6 results)

  • [Int'l Joint Research] Brown University/MD Anderson Cancer Center/Massachusetts General Hospital(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Institut Cochin INSERM(フランス)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University Hospital Ulm(ドイツ)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Seoul National University/Seoul ASAN Medical Center(韓国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Brown University/MD Anderson Cancer Center(米国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] Institut Cochin INSERM(フランス)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] University Hospital Ulm(ドイツ)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] Seoul National University/Seoul ASAN Medical Center(韓国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] Peking University(中国)

    • Related Report
      2022 Research-status Report
  • [Journal Article] RTP4 silencing provokes tumor-intrinsic resistance to immune checkpoint blockade in colorectal cancer2023

    • Author(s)
      Yamamoto Yudai、Shimada Shu、Akiyama Yoshimitsu、Tsukihara Shu、Sugimoto Raizo、Kabashima Ayano、Tokunaga Masanori、Kinugasa Yusuke、Kawakami Yutaka、Tanaka Shinji
    • Journal Title

      Journal of Gastroenterology

      Volume: ND Issue: 6 Pages: 1-14

    • DOI

      10.1007/s00535-023-01969-w

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of SFXN1 mitigates lipotoxicity and predicts poor outcome in non-viral hepatocellular carcinoma2023

    • Author(s)
      Yagi K, Shimada S, Akiyama Y, Hatano M, Asano D, Ishikawa Y, Ueda H, Watanabe S, Akahoshi K, Ono H, Tanabe M, Tanaka S.
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 9449-9449

    • DOI

      10.1038/s41598-023-36660-w

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of KDM6B epigenetically confers resistance to lipotoxicity in nonalcoholic fatty liver disease?related HCC2023

    • Author(s)
      Hatano M, Akiyama Y, Shimada S, Yagi K, Akahoshi K, Itoh M, Tanabe M, Ogawa Y, Tanaka S.
    • Journal Title

      Hepatology Communications

      Volume: 7 Issue: 10

    • DOI

      10.1097/hc9.0000000000000277

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The chronicles of hepatocellular carcinoma classification: Subtyping, modeling, and treatment2023

    • Author(s)
      Shimada S, Tanaka S.
    • Journal Title

      Hepatology

      Volume: 79 Issue: 2 Pages: 261-263

    • DOI

      10.1097/hep.0000000000000588

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GMT is frequently inactivated in pancreatic NET-G2 and is associated with the therapeutic efficacy of STZ-based regimens2023

    • Author(s)
      Yagi K, Ono H, Kudo A, Kinowaki Y, Asano D, Watanabe S, Ishikawa Y, Ueda H, Akahoshi K, Tanaka S, Tanabe M
    • Journal Title

      Scientific Reports

      Volume: - Issue: 1 Pages: 7535-7535

    • DOI

      10.1038/s41598-023-34666-y

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Surgical anatomy of the dorsal pancreatic artery: Considering embryonic development2023

    • Author(s)
      Yamane Masahiro、Ishikawa Yoshiya、Asano Daisuke、Watanabe Shuichi、Ueda Hiroki、Akahoshi Keiichi、Ono Hiroaki、Kudo Atsushi、Tanaka Shinji、Sugiyama Yuzuki、Muro Satoru、Akita Keiichi、Tanabe Minoru
    • Journal Title

      Pancreatology

      Volume: 23 Issue: 6 Pages: 697-703

    • DOI

      10.1016/j.pan.2023.07.009

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A niche-mimicking polymer hydrogel-based approach to identify molecular targets for tackling human pancreatic cancer stem cells2023

    • Author(s)
      Murota Yoshitaka、Nagane Mariko、Wu Mei、Santra Mithun、Venkateswaran Seshasailam、Tanaka Shinji、Bradley Mark、Taga Tetsuya、Tabu Kouichi
    • Journal Title

      Inflammation and Regeneration

      Volume: 43 Issue: 1 Pages: 46-46

    • DOI

      10.1186/s41232-023-00296-0

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer2023

    • Author(s)
      Ono Hiroaki、Murase Yoshiki、Yamashita Hironari、Kato Tomotaka、Asano Daisuke、Ishikawa Yoshiya、Watanabe Shuichi、Ueda Hiroki、Akahoshi Keiichi、Ogawa Kosuke、Kudo Atsushi、Akiyama Yoshimitsu、Tanaka Shinji、Tanabe Minoru
    • Journal Title

      International Journal of Oncology

      Volume: 62 Issue: 4 Pages: 51-51

    • DOI

      10.3892/ijo.2023.5499

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Incidence and Mechanism of Refractory Postoperative Cholangitis After Hepatectomy with Hepaticojejunostomy2023

    • Author(s)
      Morimoto K, Ueda H, Asano D, Ishikawa Y, Watanabe S, Akahoshi K, Ono H, Kobayashi M, Okamoto R, Tanaka S, Tanabe M.
    • Journal Title

      Journal of Gastrointestinal Surgery

      Volume: 27 Issue: 8 Pages: 1668-1676

    • DOI

      10.1007/s11605-023-05724-7

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Incidence and mechanism of refractory postoperative cholangitis after hepatectomy with hepaticojejunostomy2023

    • Author(s)
      Morimoto K, Ueda H, Asano D, Ishikawa Y, Watanabe S, Akahoshi K, Ono H, Kobayashi M, Okamoto R, Tanaka S, Tanabe M
    • Journal Title

      Journal of Gastrointestinal Surgery

      Volume: -

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune oncology in hepatocellular carcinoma.2022

    • Author(s)
      Shimada S, Tanaka S.
    • Journal Title

      International Journal of Clinical Oncology

      Volume: - Issue: 7 Pages: 1101-1109

    • DOI

      10.1007/s10147-022-02174-0

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] cGAS-STING signaling encourages immune cell overcoming of fibroblast barricades in pancreatic cancer2022

    • Author(s)
      Kabashima A, Matsuo Y, Ito S, Akiyama Y, Ishii T, Shimada S, Masamune A, Tanabe M, Tanaka S
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 10466-10466

    • DOI

      10.1038/s41598-022-14297-5

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of a novel target of <scp>SETD1A</scp> histone methyltransferase and the clinical significance in pancreatic?cancer2022

    • Author(s)
      Ishii Takeshi、Akiyama Yoshimitsu、Shimada Shu、Kabashima Ayano、Asano Daisuke、Watanabe Shuichi、Ishikawa Yoshiya、Ueda Hiroki、Akahoshi Keiichi、Ogawa Kosuke、Ono Hiroaki、Kudo Atsushi、Tanabe Minoru、Tanaka Shinji
    • Journal Title

      Cancer Science

      Volume: 114 Issue: 2 Pages: 463-476

    • DOI

      10.1111/cas.15615

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long noncoding RNA 01534 maintains cancer stemness by downregulating endoplasmic reticulum stress response in colorectal cancer2022

    • Author(s)
      Ichihara M, Takahashi H, Nishida N, Ivan C, Okuzaki D, Yokoyama Y, Ohtsuka M, Miyoshi N, Uemura M, Tanaka S, Calin G, Mori M, Doki Y, Eguchi, H, Yamamoto H
    • Journal Title

      Annals of Gastroenterological Surgery

      Volume: 7 Issue: 3 Pages: 458-470

    • DOI

      10.1002/ags3.12649

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells2021

    • Author(s)
      Kato Tomotaka、Ono Hiroaki、Fujii Mikiya、Akahoshi Keiichi、Ogura Toshiro、Ogawa Kosuke、Ban Daisuke、Kudo Atsushi、Tanaka Shinji、Tanabe Minoru
    • Journal Title

      PLOS ONE

      Volume: 16 Issue: 4 Pages: 0252917-0252917

    • DOI

      10.1007/s00432-021-03660-0

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Curative Surgery and Ki-67 Value Rather than Tumor Differentiation Predict the Survival of Patients with High-grade Neuroendocrine Neoplasms2020

    • Author(s)
      Asano Daisuke、Kudo Atsushi、Akahoshi Keiichi、Maekawa Aya、Murase Yoshiki、Ogawa Kosuke、Ono Hiroaki、Ban Daisuke、Tanaka Shinji、Tanabe Minoru
    • Journal Title

      Annals of Surgery

      Volume: Publish Ahead of Print Issue: 2 Pages: e108-e113

    • DOI

      10.1097/sla.0000000000004495

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Presentation] Metabolic Dysfunction-Associated Liver Cancer (invited lecture)2024

    • Author(s)
      Shinji Tanaka
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2024 Kyoto
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Integrated Omics Analysis for the Progression of Hepatocellular Carcinoma (invited lecture)2024

    • Author(s)
      Shinji Tanaka
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) 2024 Kyoto
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Educational Session: New currents in the field of HBP surgery2023

    • Author(s)
      Shinji Tanaka
    • Organizer
      The 35th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 基調講演:肝癌腫瘍微小環境(シンポジウム)2023

    • Author(s)
      田中真二
    • Organizer
      第59回日本肝癌研究会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Molecular and immunological mechanisms of liver cancer; preclinical studies for clinical application (Workshop)2022

    • Author(s)
      Shinji Tanaka
    • Organizer
      Asian Pacific Association for the Study of the Liver (APASL) Oncology 2022
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Biomarker research and clinical application for treatment of hepato-biliary-pancreatic cancer (Workshop)2022

    • Author(s)
      Shinji Tanaka
    • Organizer
      The 34th Meeting of Japanese Society of Hepato-Biliary-Pancreatic Surgery
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] ゲノム研究の両輪に基づく臨床応用への展開(特別企画)2022

    • Author(s)
      田中真二
    • Organizer
      第58回日本肝臓学会総会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] 外科臨床に基づく難治性がんの分子免疫機序と治療戦略(ワークショップ)2022

    • Author(s)
      田中真二
    • Organizer
      第60回日本癌治療学会学術集会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] 臨床から見た肝細胞癌の分子免疫サブタイプと治療戦略(シンポジウム)2022

    • Author(s)
      田中真二
    • Organizer
      第26回日本肝臓学会大会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Book] 肝生検ガイダンス2024

    • Author(s)
      日本肝臓学会(編集)
    • Total Pages
      88
    • Publisher
      南江堂
    • ISBN
      9784524204540
    • Related Report
      2023 Annual Research Report
  • [Remarks] 非ウイルス性肝細胞がんの特異的予後予測因子SFXN1の同定と脂肪毒性に対する耐性機序の解明

    • URL

      https://www.tmd.ac.jp/press-release/20230613-1/

    • Related Report
      2023 Annual Research Report
  • [Remarks] NAFLD関連肝がんにおける脂肪毒性への耐性獲得機序の解明

    • URL

      https://www.tmd.ac.jp/press-release/20231010-1/

    • Related Report
      2023 Annual Research Report
  • [Remarks] 分子腫瘍医学研究室ホームページ

    • URL

      https://www.tmd.ac.jp/grad/monc/

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
  • [Remarks] cGAS-STINGシグナルは免疫細胞の膵臓癌線維芽細胞バリケード突破を促進する

    • URL

      https://www.tmd.ac.jp/press-release/20220630-1/

    • Related Report
      2022 Research-status Report
  • [Remarks] 膵癌におけるエピゲノム修飾酵素SETD1Aの悪性化メカニズム解明

    • URL

      https://www.tmd.ac.jp/press-release/20221110-2/

    • Related Report
      2022 Research-status Report
  • [Remarks] 大腸癌における腫瘍細胞内因性の免疫チェックポイント阻害薬 治療抵抗性獲得メカニズムの解明

    • URL

      https://www.tmd.ac.jp/press-release/20230303-1/

    • Related Report
      2022 Research-status Report

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Published: 2022-07-05   Modified: 2025-01-30  

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