Develoment of advanced therapy targeting tumor heterogeneity in refractory cancers

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16H02670
• 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): 森 正樹 大阪大学, 医学系研究科, 教授 (70190999) ; 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) ; 深町 博史 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (70134450)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 癌 / 幹細胞 / ゲノム編集技術 / クロマチン動的変動 / クロマチン再構築 / ヒストン修飾 / 分子サブタイプ / トランスレーショナルリサーチ

Outline of Annual Research Achievements

本研究は、幹細胞可視化システムによる難治性癌の不均一性分子基盤解析と、その臨床応用を目指した先進的治療開発 という二つの視点を特徴とする。
幹細胞可視化システムを用いた解析の結果、クロマチン動的変動の不均一性により癌幹細胞転移能が制御されていることを見出し(PloS One 2016)、様々な癌腫で特徴的なクロマチン・ヒストン制御異常のサブタイプ特異性を解明するため、Crisp/Cas9ゲノム編集技術による解析を進めた(J Hepatol 2017)。ヘテロクロマチン形成を制御するDAXXは膵神経内分泌腫瘍PNETの特異的変異遺伝子として報告されたが、分子生物学的意義を解明するためゲノム編集技術を用いてDAXX欠失ヒトPNET細胞を作成した。その結果、幹細胞遺伝子プロモーター領域のヒストンH3.3メチル化を介した発現制御機序が破綻し、癌幹細胞性・造腫瘍性を惹起することを見出した(Endocr Relat Cancer 2018)。ヒストン修飾因子KDM6Aは予後不良膵癌サブタイプに特徴的な変異遺伝子として報告されたが、我々はゲノム編集技術を用いてKDM6A欠失ヒト膵癌細胞を作成し、ヒストンアセチル化酵素p300による癌抑制遺伝子の阻害機序(COMPASS複合体)が破綻して癌幹細胞性・造腫瘍性を惹起すること、ヒストン脱アセチル化酵素HDAC阻害剤が特異的に著効することを見出し、サブタイプ特異的治療の可能性を明らかにした(Int J Cancer 2019)。さらにレンチウイルスベクターを用いた高効率ゲノム編集技術を新たに開発し、肝癌におけるロイシン欠乏性オートファジー因子DEPDC5(Sci Rep 2018)、胃癌におけるヒストン修飾因子PRMT6(Carcinogenesis 2019)など新規遺伝子異常メカニズムを解明し、分子サブタイプ特異的治療の開発へと展開している。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Brown University(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Brown University
• [Int'l Joint Research] Seoul National University/Korea Res Inst Biosci Biotech(韓国)
  • Country Name: KOREA (REP. OF KOREA)
  • Counterpart Institution: Seoul National University/Korea Res Inst Biosci Biotech
• [Journal Article] Comprehensive molecular and immunological characterization of hepatocellular carcinoma (2019)
  • Author(s): Shimada S, Mogushi K, Akiyama Y, Furuyama T, Watanabe S, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Arii S, Tanabe M, Wands JR, Tanaka S.
  • Journal Title: EBioMedicine Volume: 40 Pages: 457～470
  • DOI: 10.1016/j.ebiom.2018.12.058
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Asymmetric dimethylation at histone H3 arginine 2 by PRMT6 in gastric cancer progression (2019)
  • Author(s): Okuno K, Akiyama Y, Shimada S, Nakagawa M, Tanioka T, Inokuchi M, Yamaoka S, Kojima K, Tanaka S.
  • Journal Title: Carcinogenesis Volume: 40 Pages: 15～26
  • DOI: 10.1093/carcin/bgy147
  • Peer Reviewed
• [Journal Article] A subset of diffuse-type gastric cancer is susceptible to mTOR inhibitors and checkpoint inhibitors (2019)
  • Author(s): Fukamachi H, Kim S-K, Koh J, Lee HS, Sasaki Y, Yamashita K, Nishikawaji T, Shimada S, Akiyama Y, Byeon SJ, Bae DH, Okuno K, Nakagawa M, Tanioka T, Inokuchi M, Kawachi H, Tuchiya K, Kojima K, Tokino T, Eishi Y, Kim YS, Kim WH, Yuasa Y, Tanaka S
  • Journal Title: Journal of Experimental & Clinical Cancer Research Volume: 38 Pages: 127
  • DOI: 10.1186/s13046-019-1121-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality (2019)
  • Author(s): Watanabe S, Shimada S, Akiyama Y, Ishikawa Y, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Yamaoka S, Tanabe M, Tanaka S.
  • Journal Title: International Journal of Cancer Volume: 145 Pages: 192～205
  • DOI: 10.1002/ijc.32072
  • Peer Reviewed
• [Journal Article] Downregulated Pancreatic Beta Cell Genes Indicate Poor Prognosis in Patients With Pancreatic Neuroendocrine Neoplasms (2019)
  • Author(s): Kudo A, Akahoshi K, Ito S, Akashi T, Shimada S, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Tateishi U, Tanaka S, Tanabe M.
  • Journal Title: Annals of Surgery Volume: - Pages: in press
  • DOI: 10.1097/SLA.0000000000002911
  • Peer Reviewed
• [Journal Article] Orotate phosphoribosyltransferase as a predictor of benefit from S-1 adjuvant chemotherapy for cholangiocarcinoma patients (2019)
  • Author(s): Akahoshi K, Ban D, Kuboki R, Oba A, Ono H, Mitsunori Y, Kudo A, Tanaka S, Tanabe M.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Pages: in press
  • DOI: 10.1111/jgh.14477
  • Peer Reviewed
• [Journal Article] A new era for understanding genetic evolution of multistep carcinogenesis (2019)
  • Author(s): Shimada S, Tanaka S.
  • Journal Title: Journal of Gastroenterology Volume: - Pages: in press
  • DOI: 10.1007/s00535-019-01576-8
  • Peer Reviewed
• [Journal Article] A simple and practical index predicting the prognoses of the patients with well-differentiated pancreatic neuroendocrine neoplasms (2019)
  • Author(s): Liu B, Kudo A, Kinowaki Y, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Tanaka S, Akashi T, Tanabe M.
  • Journal Title: Journal of Gastroenterology Volume: - Pages: in press
  • DOI: 10.1007/s00535-019-01570-0
  • Peer Reviewed
• [Journal Article] The clinical implications of peripancreatic fluid collection after distal pancreatectomy (2019)
  • Author(s): Yoshino J, Ban D, Ogura T, Ogawa K, Ono H, Mitsunori Y, Kudo A, Tanaka S, Tanabe M
  • Journal Title: World Journal of Surgery Volume: - Pages: in press
  • Peer Reviewed / Open Access
• [Journal Article] Precision medicine based on surgical oncology in the era of genome-scale analysis and genome editing technology (2018)
  • Author(s): Tanaka S.
  • Journal Title: Annals of Gastroenterological Surgery Volume: 2 Pages: 106～115
  • DOI: 10.1002/ags3.12059
  • Peer Reviewed / Open Access
• [Journal Article] DEPDC5 deficiency contributes to resistance to leucine starvation via p62 accumulation in hepatocellular carcinoma (2018)
  • Author(s): Mizuno Y, Shimada S, Akiyama Y, Watanabe S, Aida T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Arii S, Yamaoka S, Tanabe M, Tanaka S.
  • Journal Title: Scientific Reports Volume: 8 Pages: 106
  • DOI: 10.1038/s41598-017-18323-9
  • Peer Reviewed / Open Access
• [Journal Article] Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models (2018)
  • Author(s): Shimada S, Akiyama Y, Mogushi K, Ishigami-Yuasa M, Kagechika H, Nagasaki H, Fukamachi H, Yuasa Y, Tanaka S.
  • Journal Title: British Journal of Cancer Volume: 118 Pages: 972～984
  • DOI: 10.1038/s41416-018-0008-y
  • Peer Reviewed
• [Journal Article] Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors (2018)
  • Author(s): Chiyonobu N, Shimada S, Akiyama Y, Mogushi K, Itoh M, Akahoshi K, Matsumura S, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Arii S, Suganami S, Yamaoka S, Ogawa Y, Tanabe M, Tanaka S.
  • Journal Title: The American Journal of Pathology Volume: 188 Pages: 1213～1224
  • DOI: 10.1016/j.ajpath.2018.01.012
  • Peer Reviewed
• [Journal Article] Tumor suppressor functions of DAXX through histone H3.3/H3K9me3 pathway in pancreatic NETs (2018)
  • Author(s): Ueda H, Akiyama Y, Shimada S, Serizawa M, Mogushi K, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Kudo A, Tanabe M, Tanaka S.
  • Journal Title: Endocrine-Related Cancer Volume: 25 Pages: 619～631
  • DOI: 10.1530/ERC-17-0328
  • Peer Reviewed
• [Journal Article] Sunitinib shrinks NET-G3 pancreatic neuroendocrine neoplasms (2018)
  • Author(s): Mizuno Y, Kudo A, Akahoshi K, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Akashi T, Tateishi U, Tanaka S, Tanabe M.
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 144 Pages: 1155～1163
  • DOI: 10.1007/s00432-018-2636-2
  • Peer Reviewed
• [Journal Article] Rapid growth speed of cysts can predict malignant intraductal mucinous papillary neoplasms (2018)
  • Author(s): Akahoshi K, Ono H, Akasu M, Ban D, Kudo A, Atsuko Konta A, Tanaka S, Tanabe M.
  • Journal Title: Journal of Surgical Research Volume: 231 Pages: 195～200
  • DOI: 10.1016/j.jss.2018.05.056
  • Peer Reviewed
• [Journal Article] Splenic artery as a simple landmark indicating difficulty during laparoscopic distal pancreatectomy (2018)
  • Author(s): Ishikawa Y, Ban D, Matsumura S, Watanabe S, Akahoshi K, Ono H, Mitsunori Y, Ochiai T, Kudo A, Tanaka S, Tanabe M.
  • Journal Title: Asian Journal of Endoscopic Surgery Volume: 12 Pages: 81～87
  • DOI: 10.1111/ases.12485
  • Peer Reviewed
• [Journal Article] Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells (2018)
  • Author(s): Tamari K, KonnoM , Asai A, Koseki J, Hayashi K, Kawamoto K, Murai N, Matsufuji S, Isohashi F, Satoh T, Gotoh N, Tanaka S, Doki Y, Mori M, Ogawa K, Ishii H.
  • Journal Title: Cell Death Discovery Volume: 4 Pages: 104
  • DOI: 10.1038/s41420-018-0117-7
  • Peer Reviewed / Open Access
• [Presentation] Precision medicine for HCC and pancreatic cancer (Symposium) (2018)
  • Author(s): Shinji Tanaka
  • Organizer: The 7th International Forum of The Japanese Society of Gastroenterology Jointly with the 12th International Symposium on ALPD and Cirrhosis
  • Int'l Joint Research / Invited
• [Presentation] Precision immunotherapy for hypermutator and immunogenic subtypes of hepatocellular carcinoma (Workshop) (2018)
  • Author(s): Shinji Tanaka, Atsushi Oba, Shu Shimada, Yoshimitsu Akiyama, Kosuke Ogawa, Hiroaki Ono, Yusuke Mitsunori, Daisuke Ban, Atsushi Kudo, Shigeki Arii, Minoru Tanabe
  • Organizer: 73rd General Meeting of the Japanese Society of Gastroenterological Surgery
  • Int'l Joint Research
• [Presentation] Molecular target therapy for liver cancer under precision medicine (Symposium) (2018)
  • Author(s): Shinji Tanaka
  • Organizer: 77th Annual Meeting of Japanese Cancer Association
  • Int'l Joint Research / 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（シンポジウム） (2018)
  • Author(s): 田中真二
  • Organizer: 第39回日本肥満学会
  • Invited
• [Presentation] 肝癌の予後不良サブタイプの同定とゲノム編集による治療戦略（ワークショップ） (2018)
  • Author(s): 田中真二、水野裕貴、田邉稔
  • Organizer: 第16回日本消化器外科学会大会
• [Presentation] 代謝関連肝癌の特異的バイオマーカーおよび治療標的の同定（ワークショップ） (2018)
  • Author(s): 田中真二、小川佳宏、田邉稔
  • Organizer: 第22回日本肝臓学会大会
• [Book] Molecular analysis for therapeutic targets of pancreatic cancer. IN: Molecular diagnosis and targeting for thoracic and gastrointestinal malignancy (2018)
  • Author(s): Tanaka S. (eds. Shimada Y, Yanaga K)
  • Total Pages: 18/156
  • Publisher: Springer
• [Remarks] 胃がんにおいてヒストン修飾の異常により悪性度を増すメカニズムを解明
  • URL: hhttp://www.tmd.ac.jp/archive-tmdu/kouhou/20181204_2.pdf
• [Remarks] 予後不良膵癌サブタイプにおけるヒストン修飾遺伝子の不活化の意義を解明
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20181218_1.pdf
• [Remarks] 肝細胞癌の分子生物学的・免疫学的サブタイプ分類を確立
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20190111_1.pdf
• [Remarks] New liver cancer subtypes revealed immunologically
  • URL: https://www.eurekalert.org/pub_releases/2019-02/tmad-ctd020119.php
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/monc/