Innovation of genome editing technology as the basis to develop molecular subtype panels of intractable cancer
Project/Area Number |
18K19575
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 55:Surgery of the organs maintaining homeostasis and related fields
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Research Institution | Tokyo 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)
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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)
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Project Period (FY) |
2018-06-29 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
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Keywords | 癌 / 多様性 / ゲノム医療 / ゲノム編集 / 免疫治療 / エキソンスキッピング / 分子サブタイプ分類 / プレシジョンメディシン / 分子サブタイプ / 難治性がん / レンチウイルス |
Outline of Final Research Achievements |
In this project, a novel multiplex genome editing technology was developed for simultaneous edition of multiple genes with high efficiency. The genome editing analyses revealed that PRMT6 is required for cancer invasion through increased H3R2me2as level (Carcinogenesis 2019), and ARID1A-mutated cancer exhibits a stemness phenotype with histone methylation (Carcinogenesis, in press). In addition, we synthesized CTNNB1-exon 3 skipping mutant clones by double genome editing of intron 2 and intron 3 in CTNNB1 gene encoding β-catenin. Since the exon 3 encodes the region regulating β-catenin stability, the in-frame exon 3 skipping resulted in the enhancement of β-catenin signals, and noteworthy, the immunosuppressive effects. Our clinical analysis has clarified that CTNNB1-mutated cancer is characterized as an immunologically “cold” subtype (EBioMedicine 2019), and it provides the essential system for development of immune combination therapy by identifying a new therapeutic target.
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Academic Significance and Societal Importance of the Research Achievements |
近年の癌ゲノム研究によって分子サブタイプ分類が進み、ゲノム医療・プレシジョンメディシンへの応用が期待されている。しかしながら、その分子生物学的意義が不明なため、治療開発には至っていない。 本研究では高効率の多重ゲノム編集技術を開発することに成功し、同時に複数遺伝子を編集する画期的成果が得られた。癌細胞には多くの遺伝子変異が蓄積しており、多重ゲノム編集によって、分子サブタイプの解明のみならず、同系マウスがん細胞パネルの構築が可能となり、免疫チェックポイント阻害との併用解析など新規治療開発へ応用できる。実臨床を目指したプレシジョンメディシン実装化のブレークスルーとなる挑戦的かつ戦略的研究課題である。
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Report
(3 results)
Research Products
(49 results)
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[Journal Article] Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations.2020
Author(s)
Fujita M, Yamaguchi R, Hasegawa T, Shimada S, Arihiro K, Hayashi S, Maejima K, Nakano K, Fujimoto A, Ono A, Aikata H, Ueno M, Hayami S, Tanaka H, Miyano S, Yamaue H, Chayama K, Kakimi K, Tanaka S, Imoto S, Nakagawa H.
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Journal Title
EBioMedicine
Volume: 53
Pages: 102659-102659
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Loss of ARID1A induces a stemness gene ALDH1A1 expression with histone acetylation in the malignant subtype of cholangiocarcinoma.2020
Author(s)
Yoshino J, Akiyama Y, Shimada S, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Kudo A, Yamaoka S, Tanabe M, Tanaka S.
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Journal Title
Carcinogenesis
Volume: in press
Issue: 6
Pages: 0000-0000
DOI
Related Report
Peer Reviewed / Open Access
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[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.
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Journal Title
J Gastroenterol.
Volume: -
Issue: 9
Pages: 819-828
DOI
Related Report
Peer Reviewed
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[Journal Article] E-cad-Fc-matrix enhances cancer stem-like properties and induces mesenchymal features in colon cancer cells.2019
Author(s)
Qian Y, Wu X, Yokoyama Y, Okuzaki D, Taguchi M, Hirose H, Wang J, Hata T, Inoue A, Hiraki M, Ohtsuka M, Takahashi H, Haraguchi N, Mizushima T, Tanaka S, Mori M, Yamamoto H.
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Journal Title
Cancer Science
Volume: 110
Issue: 11
Pages: 3520-3532
DOI
Related Report
Peer Reviewed
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[Journal Article] Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis2019
Author(s)
Asakawa M, Itoh M, Suganami T, Sakai T, Kanai S, Shirakawa I, Yuan X, Hatayama T, Shimada S, Akiyama Y, Fujiu K, Inagaki Y, Manabe I, Yamaoka S, Yamada T, Tanaka S, Ogawa Y.
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Journal Title
Sci Rep.
Volume: 9
Issue: 1
Pages: 19601-19601
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Comprehensive molecular characterization of liver cancer and inheritance of the phenotypic traits during tumor recurrence.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.
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Journal Title
EBioMedicine
Volume: 40
Pages: 457-470
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality2019
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.
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Journal Title
International Journal of Cancer
Volume: -
Issue: 1
Pages: 192-205
DOI
Related Report
Peer Reviewed
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[Journal Article] Downregulated Pancreatic Beta Cell Genes Indicate Poor Prognosis in Patients With Pancreatic Neuroendocrine Neoplasms.2018
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.
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Journal Title
Ann Surg.
Volume: -
Issue: 4
Pages: 732-739
DOI
Related Report
Peer Reviewed
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[Journal Article] DEPDC5 deficiency contributes to resistance to leucine starvation via p62 accumulation in hepatocellular carcinoma2018
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
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Journal Title
Scientific Reports
Volume: 8
Issue: 1
Pages: 106-106
DOI
Related Report
Peer Reviewed / Open Access
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[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, Mogushi K, Serizawa M, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Kudo A, Tanabe M, Tanaka S.
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Journal Title
Endocr Relat Cancer
Volume: 25(6)
Issue: 6
Pages: 619-631
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Polyamine flux suppresses histone lysine demethylases and enhances ID1 expression in cancer stem cells2018
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.
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Journal Title
Cell Death Discovery
Volume: 4
Issue: 104
Pages: 104-104
DOI
Related Report
Peer Reviewed / Open Access
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[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
Related Report
Int'l Joint Research
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