Clarification of diversity mechanisms for innovation of refractory cancer treatment

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19H01055
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 田中 真二 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): 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) ; 新部 彩乃 (樺嶋) 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (20445448) ; 森 正樹 東海大学, 医学部, 教授 (70190999)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 多様性 / サブタイプ / がん幹細胞 / ゲノム医療 / 免疫治療 / ゲノム編集 / オルガノイド / 樹状細胞活性化

Outline of Annual Research Achievements

難治性消化器癌のサブタイプ多様性とがん幹細胞多様性の解明に基づく先端的治療開発を目的として、(１)難治性がんサブタイプの多重ゲノム編集解析と治療開発、(２)がん幹細胞の生体内治療抵抗性因子を標的とした治療開発の二課題で構成する。先端的治療開発に加え、多施設臨床検体データを用いて前向き検証するシステムを備えている。がん多様性解明と臨床検体検証を基盤として、難治性消化器癌治療へ展開する実践的課題である。
我々は臨床検体解析にてCTNNB1変異サブタイプが著しい免疫排除を呈することを報告しており(Shimada, Tanaka et al. EBioMedicine 2019)、本研究では多重ゲノム編集を応用してexon skippingによるin-frame変異を導入し、ヒト・マウスCTNNB1内因性変異肝癌細胞を構築した。オルガノイド免疫相互作用および同系統マウスモデル解析の結果、樹状細胞活性化ケモカインの発現阻害により腫瘍免疫反応が抑制されることを見出した。ヒト臨床検体にてCTNNB1変異サブタイプ特異的な樹状細胞活性化ケモカイン発現低下を検出し、ケモカイン遺伝子導入によりCTNNB1変異肝癌の免疫賦活化が誘導されることを明らかにした(Akasu, Tanaka et al. Sci Rep 2021)。CTNNB1変異肝癌では免疫チェックポイント阻害剤が無効であるという臨床結果や(Clin Cancer Res 2019)、樹状細胞活性化ケモカインによる抗腫瘍効果が報告されており(Cancer Discov 2019)、サブタイプ特異的複合免疫治療開発の可能性が示唆された(Shimada, Tanaka. IJCO, in press）。現在、転移性肝癌、転移性膵癌、スキルス胃癌などを多重ゲノム編集およびRNA編集にて作成し、がん幹細胞性を制御する新規治療開発を進めている。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Remarks

分子腫瘍医学研究室ホームページ
http://www.tmd.ac.jp/grad/monc/

Research Products

• [Int'l Joint Research] Brown University/MD Anderson Cancer Center(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Brown University/MD Anderson Cancer Center
• [Int'l Joint Research] Institut Cochin INSERM(フランス)
  • Country Name: FRANCE
  • Counterpart Institution: Institut Cochin INSERM
• [Int'l Joint Research] Seoul ASAN Medical Center/Seoul National University(韓国)
  • Country Name: KOREA (REP. OF KOREA)
  • Counterpart Institution: Seoul ASAN Medical Center/Seoul National University
• [Int'l Joint Research] Peking University(中国)
  • Country Name: CHINA
  • Counterpart Institution: Peking University
• [Journal Article] Genomic landscape of a mouse model of diffuse-type gastric adenocarcinoma (2022)
  • Author(s): Zhang M, Sugita I, Komura D, Katoh H, Shimada S, Inazawa J, Tanaka S, Ishikawa S.
  • Journal Title: Gastric Cancer Volume: 25 Pages: 83-95
  • DOI: 10.1007/s10120-021-01226-0
  • Peer Reviewed
• [Journal Article] Functional assessment of miR?1291 in colon cancer cells (2022)
  • Author(s): Wang J, Hirose H, Yokoyama Y, Ikeshima R, Tsujimura N, Bonkobara S, Takeda K, Hata T, Inoue A, Hiraki M, Ohtsuka M, Nishida N, Takahashi H, Haraguchi N, Tanaka S, Wu X, Mori M, Yamamoto H.
  • Journal Title: International Journal of Oncology Volume: 60 Pages: 13
  • DOI: 10.3892/ijo.2022.5303
  • Peer Reviewed
• [Journal Article] Hormonal tumor mapping for liver metastases of gastroenteropancreatic neuroendocrine neoplasms: a novel therapeutic strategy (2022)
  • Author(s): Maekawa A, Kudo A, Kishino Mitsuhiro, Murase Y, Watanabe S, Ishikawa Y, Ueda Hiroki, Akahoshi K, Ogawa K, Ono H, Tanaka S, Kinowaki Y, Tanabe M.
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 148 Pages: 697-706
  • DOI: 10.1007/s00432-021-03650-2
  • Peer Reviewed
• [Journal Article] A novel classification of portal venous tumor invasion to predict residual tumor status after surgery in patients with pancreatic neuroendocrine neoplasms (2022)
  • Author(s): Kato T, Kudo A, Ishikawa Y, Watanabe S, Akahoshi K, Ogawa K, Ono H, Ban D, Tanaka S, Tanabe M.
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 148 Pages: 931-941
  • DOI: 10.1007/s00432-021-03660-0
  • Peer Reviewed
• [Journal Article] Curative Surgery and Ki-67 Value Rather than Tumor Differentiation Predict the Survival of Patients with High-grade Neuroendocrine Neoplasms (2022)
  • Author(s): Asano D, Kudo A, Akahoshi K, Ogawa K, Ono H, Ban D, Tanaka S, Tanabe M.
  • Journal Title: Annals of Surgery Volume: - Pages: in press
  • DOI: 10.1097/SLA.0000000000004495
  • 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: - Pages: in press
  • DOI: 10.1007/s10147-022-02174-0
  • Peer Reviewed
• [Journal Article] Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma (2021)
  • Author(s): Akasu M, Shimada S, Kabashima A, Akiyama Y, Shimokawa M, Akahoshi K, Kudo A, Yamaoka S, Tanabe M, Tanaka S.
  • Journal Title: Scientific Reports Volume: 11 Pages: 16732
  • DOI: 10.1038/s41598-021-96167-0
  • Peer Reviewed / Open Access
• [Journal Article] Arterial chemoembolisation with cisplatin versus epirubicin for hepatocellular carcinoma (ACE 500 study): A multicentre, randomised controlled phase 2/3 trial (2021)
  • Author(s): Aramaki O, Takayama T, Moriguchi M, Sakamoto H, Yodono H, Kokudo N, Yamanaka N, Kawasaki S, Sasaki Y, Kubota K, Otsuji E, Tanaka S, Matsuyama Y, Fujii M, for the ACE500 study group.
  • Journal Title: European Journal of Cancer Volume: 157 Pages: 373-382
  • DOI: 10.1016/j.ejca.2021.08.027
  • Peer Reviewed
• [Journal Article] Surgery after sunitinib administration to improve survival of patients with advanced pancreatic neuroendocrine neoplasms (2021)
  • Author(s): Murase Y, Kudo A, Akahoshi K, Maekawa A, Ishikawa Y, Ueda H, Ogawa K, Ono H, Tanaka S, Tanabe M.
  • Journal Title: Annals of Gastroenterological Surgery Volume: 5 Pages: 692-700
  • DOI: 10.1002/ags3.12458
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic distal pancreatectomy in a patient with aberrant splenic artery originating from the superior mesenteric artery (2021)
  • Author(s): Ishida H, Ishikawa Y, Akahoshi K, Ueda H, Morimoto K, Yamashita H, Ogawa K, Ono H, Kudo A, Tanaka S, Tanabe M.
  • Journal Title: Medicine Volume: 100 Pages: e25704
  • DOI: 10.1097/MD.0000000000025704
  • Peer Reviewed
• [Journal Article] Prediction of early recurrence of pancreatic ductal adenocarcinoma after resection (2021)
  • Author(s): Sugawara T, Ban D, Nishino J, Watanabe S, Ishikawa Y, Akahoshi K, Ogawa K, Ono H, Kudo A, Tanaka S, Tanabe M.
  • Journal Title: PLOS ONE Volume: 16 Pages: e0249885
  • DOI: 10.1371/journal.pone.0249885
  • Peer Reviewed / Open Access
• [Journal Article] Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells (2021)
  • Author(s): Kato T, Ono H, Fujii M, Y, Akahoshi K, Ogura T, Ogawa K, Ban D, Kudo A, Tanaka S, Tanabe M.
  • Journal Title: PLOS ONE Volume: 16 Pages: e0252917
  • DOI: 10.1371/journal.pone.0252917
  • Peer Reviewed / Open Access
• [Journal Article] C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer (2021)
  • Author(s): Ono H, Kato T, Murase Y, Nakamura Y, Ishikawa Y, Watanabe S, Akahoshi K, Ogura T, Ogawa K, Ban D, Kudo A, Akiyama Y, Tanaka S, Ito H, Tanabe M.
  • Journal Title: Scientific Reports Volume: 11 Pages: 10078
  • DOI: 10.1038/s41598-021-89530-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of acid ceramidase elicits mitochondrial dysfunction and oxidative stress in pancreatic cancer cells (2021)
  • Author(s): Taniai T, Shirai Y, Shimada Y, Hamura R, Yanagaki M, Takada N, Horiuchi T, Haruki K, Furukawa K, Tsuboi K, Okamoto Y, Shimada S, Tanaka S, Ohashi T, Ikegami T.
  • Journal Title: Cancer Science Volume: 112 Pages: 4570-4579
  • DOI: 10.1111/cas.15123
  • Peer Reviewed
• [Journal Article] Inhibitor library screening identifies ispinesib as a new potential chemotherapeutic agent for pancreatic cancers (2021)
  • Author(s): Murase Y, Ono H, Ogawa K, Yoshioka R, Ishikawa Y, Ueda H, Akahoshi K, Ban D, Kudo A, Tanaka S, Tanabe M.
  • Journal Title: Cancer Science Volume: 112 Pages: 4641-4654
  • DOI: 10.1111/cas.15134
  • Peer Reviewed
• [Presentation] Surgical oncology to develop novel targeted and immunotherapies for hepato-biliary-pancreatic cancer (Award Session) (2021)
  • Author(s): Shinji Tanaka
  • Organizer: 80th Annual Meeting of Japanese Cancer Association
  • Int'l Joint Research / Invited
• [Presentation] Stemness and heterogeneity of liver cancer (2021)
  • Author(s): Shinji Tanaka
  • Organizer: JSH International Liver Conference 2021
  • Int'l Joint Research / Invited
• [Presentation] 多様性と科学の発展 (2021)
  • Author(s): 田中真二
  • Organizer: 第25回日本心療内科学会学術大会
  • Invited
• [Presentation] 肝臓外科からみた代謝関連肝癌の分子機序と治療戦略 (2021)
  • Author(s): 田中真二、島田周、秋山好光、新部彩乃、波多野恵、下川雅弘、田邉稔、小川佳宏
  • Organizer: 第7回肝臓と糖尿病・代謝研究会
  • Invited
• [Remarks] β-catenin活性化型肝がんの免疫回避機構を解明
  • URL: https://www.tmd.ac.jp/press-release/20210824-1/