Multi-regional analysis and the simulation of evolution elucidate the intra-tumor diversity of colorectal cancer.
Publicly Offered Research
Project Area | Integrated analysis and regulation of cellular diversity |
Project/Area Number |
20H05039
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Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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Allocation Type | Single-year Grants |
Review Section |
Complex systems
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Research Institution | Kyushu University |
Principal Investigator |
三森 功士 九州大学, 大学病院, 教授 (50322748)
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Project Period (FY) |
2020-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2020: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
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Keywords | 大腸癌 / ゲノム進化 / 腫瘍免疫応答 / 免疫逃避 / APM / 進化 / HLA / ダーウイン進化 / 中立進化 / コピー数変異 / シミュレーション / 早期大腸がん |
Outline of Research at the Start |
がんの腫瘍内ダイバーシティーを生み出す進化のダイナミクスを理解することは重要である。これまでに我々はMSS大腸がんの腫瘍内ダイバーシティーの再現進化モデルの構築に成功した。本研究では、(1)MSS大腸がん、(2)陥凹型大腸がん、(3)MSI-H大腸がんを対象に、ゲノムレベルの多領域データに加え腫瘍免疫微小環境データも取得する。それらを元に進化系統樹を推定し、シミュレーション解析に各サブタイプの進化モデルを構築する。すなわちゲノムレベルおよびがん-免疫細胞間相互作用を勘案した上で主要な三つの大腸がんサブタイプについての詳細な進化モデルの構築を行い、腫瘍内ダイバーシティーの理解を深化させる。
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Outline of Annual Research Achievements |
がんの腫瘍内ダイバーシティ(多様性)はがん難治性の一因であり、それを生み出すがんの進化のダイナミクスを理解することは臨床的にも重要である。われわれはMSS大腸がんを対象に多領域シーケンス解析を行い、早期大腸癌と進行大腸がんにおいて異なる進化様式から発生する腫瘍内多様性が存在することをシミュレーションで明らかにした。本研究でわれわれはMSS大腸がんの4サブタイプのうち特にMSI-H大腸がんについてゲノム進化を解析し、多領域データに加え腫瘍免疫微小環境を解析した。 MSI-H大腸がん症例における腫瘍内不均一性についてMSI-H CRCのゲノム解析とマルチサンプリングによるがん進化の数理モデリングを組み合わせた研究を行った。まず、246例のMSI-H 大腸がんの公開全エクソームシーケンス(WES)データを解析し、ゲノム変化がHLAクラスI遺伝子やB2Mなどの抗原提示機構(APM)に極めて濃縮されていることを明らかにした。さらに、6つのMSI-H 大腸がんの多領域WESにより、腫瘍内不均一性(ITH)を明らかにし、APM変異の多くがサブクローン変異として獲得されていることを明らかにした。また、サブクローナルな変異アレル頻度はMSS腫瘍に比べてMSI-H腫瘍で高い傾向にあり、サブクローナル変異は陽性選択を受けていることが示唆された。本件に関しては現在さらなる解析を行っている。また、MSI-Hにおける抗原提示機構の破綻を伴う進化とがん微小環境との関係性については現在鋭意解析を続けているところである。最後に、多領域解析データをもとにしたシミュレーションによりサブクローンの免疫逃避機構を伴うMSI-H 大腸がんの進化過程を明らかにした。すなわちMSI-H 大腸がんはサブクローナルな免疫逃避機構を頻繁に獲得し、それがダーウィン選択によって広範なITHの形成に寄与していることを示した。
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Research Progress Status |
令和3年度が最終年度であるため、記入しない。
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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。
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Report
(2 results)
Research Products
(79 results)
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[Journal Article] Nano-scale physical properties characteristic to metastatic intestinal cancer cells identified by high-speed scanning ion conductance microscope.2022
Author(s)
Wang D, Sun L, Okuda S, Yamamoto D, Nakayama M, Oshima H, Saito H, Kouyama Y, Mimori K, Ando T, Watanabe S, Oshima M.
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Journal Title
Biomaterials.
Volume: 280
Pages: 121256-121256
Related Report
Peer Reviewed / Open Access
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[Journal Article] Fanconi Anemia Complementation Group E, a DNA Repair-Related Gene, Is a Potential Marker of Poor Prognosis in Hepatocellular Carcinoma.2022
Author(s)
Takahashi J, Masuda T, Kitagawa A, Tobo T, Nakano Y, Abe T, Ando Y, Kosai K, Kobayashi Y, Matsumoto Y, Yoshizumi T, Mori M, Mimori K.
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Journal Title
Oncology.
Volume: 100(2)
Issue: 2
Pages: 101-113
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] GET4 is a novel driver gene in colorectal cancer that regulates the localization of BAG6, a nucleocytoplasmic shuttling protein.2022
Author(s)
Koike K, Masuda T, Sato K, Fujii A, Wakiyama H, Tobo T, Takahashi J, Motomura Y, Nakano T, Saito H, Matsumoto Y, Otsu H, Takeishi K, Yonemura Y, Mimori K, Nakagawa T.
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Journal Title
Cancer Sci.
Volume: 113(1)
Issue: 1
Pages: 156-169
DOI
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Peer Reviewed / Open Access
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[Journal Article] Pan-cancer methylome analysis for cancer diagnosis and classification of cancer cell of origin.2021
Author(s)
Shimizu D, Taniue K, Matsui Y, Haeno H, Araki H, Miura F, Fukunaga M, Shiraishi K, Miyamoto Y, Tsukamoto S, Komine A, Kobayashi Y, Kitagawa A, Yoshikawa Y, Sato K, Saito T, Ito S, Masuda T, Niida A, Suzuki M, Baba H, Ito T, Akimitsu N, Kodera Y, Mimori K.
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Journal Title
Cancer Gene Ther.
Volume: Epub
Issue: 5
Pages: 1-1
DOI
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Peer Reviewed / Open Access
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[Journal Article] Clinical Significance of Acylphosphatase 1 Expression in Combined HCC-iCCA, HCC, and iCCA.2021
Author(s)
Sakano Y, Noda T, Kobayashi S, Kitagawa A, Iwagami Y, Yamada D, Tomimaru Y, Akita H, Gotoh K, Asaoka T, Tanemura M, Umeshita K, Mimori K, Doki Y, Eguchi H.
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Journal Title
Dig Dis Sci.
Volume: Epub
Issue: 8
Pages: 3817-3830
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Evolving Genomic Landscape of Esophageal Squamous Cell Carcinoma Under Chemoradiotherapy.2021
Author(s)
Hirata H,...Masuda T, Saito T, Kageyama SI, Motomura Y, Ito S, Yoshitake T, Tsurumaru D, Nishimuta Y, Yokoyama A, Hasegawa T, Chiba K, Shiraishi Y, Du J, Miura F, Morita M, Toh Y, Hirakawa M, Shioyama Y, Ito T, Akimoto T, Miyano S, Shibata T, Mori M, Suzuki Y, Ogawa S, Ishigami K, Mimori K.
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Journal Title
Cancer Res.
Volume: 81(19)
Issue: 19
Pages: 4926-4938
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Oxysterol binding protein-like 3 (OSBPL3) is a novel driver gene that promotes tumor growth in part through R-Ras/Akt signaling in gastric cancer.2021
Author(s)
Hu Q, Masuda T, Koike K, Sato K, Tobo T, Kuramitsu S, Kitagawa A, Fujii A, Noda M, Tsuruda Y, Otsu H, Kuroda Y, Ito S, Oki E, Mimori K.
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Journal Title
Sci Rep.
Volume: 11(1)
Issue: 1
Pages: 19178-19178
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model.2021
Author(s)
Ono H, Arai Y, Furukawa E, Narushima D, Matsuura T, Nakamura H, Shiokawa D, Nagai M, Imai T, Mimori K, Okamoto K, Hippo Y, Shibata T, Kato M.
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Journal Title
BMC Biol
Volume: 19(1)
Issue: 1
Pages: 207-207
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA.2021
Author(s)
Sunami K, Bando H, Yatabe Y, Naito Y, Takahashi H, Tsuchihara K, Toyooka S, Mimori K, Kohsaka S, Uetake H, Kinoshita I, Komine K, Takeda M, Hayashida T, Tamura K, Nishio K, Yamamoto N; Working Group of a Joint Task Force of Three Academic Societies for the Promotion of Cancer Genomic Medicine.
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Journal Title
Cancer Sci.
Volume: 112(9)
Issue: 9
Pages: 3911-3917
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer.2021
Author(s)
Kobayashi Y, Masuda T, Fujii A, Shimizu D, Sato K, Kitagawa A, Tobo T, Ozato Y, Saito H, Kuramitsu S, Noda M, Otsu H, Mizushima T, Doki Y, Eguchi H, Mori M, Mimori K.
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Journal Title
Cancer Sci.
Volume: 112(8)
Issue: 8
Pages: 3173-3189
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cancer-associated Fibroblast-derived Spondin-2 Promotes Motility of Gastric Cancer Cells. Cancer Genomics Proteomics.2021
Author(s)
Kuramitsu S, Masuda T, Hu Q, Tobo T, Yashiro M, Fujii A, Kitagawa A, Abe T, Otsu H, Ito S, Oki E, Mori M, Mimori K.
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Journal Title
Cancer Genomics Proteomics.
Volume: 18(4)
Issue: 4
Pages: 521-529
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cytolytic activity score as a biomarker for antitumor immunity and clinical outcome in patients with gastric cancer2021
Author(s)
Qingjiang Hu 1 , Kentaro Nonaka 1 , Hiroaki Wakiyama 2 , Yu Miyashita 1 , Yoshiaki Fujimoto 1 , Tomoko Jogo 1 , Kentaro Hokonohara 1 , Ryota Nakanishi 1 , Yuichi Hisamatsu 1 , Koji Ando 1 , Yasue Kimura 1 , Takaaki Masuda 2 , Eiji Oki 1 , Koshi Mimori 2 , Yoshinao Oda 3 , Masaki Mori 1
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Journal Title
Cancer Med.
Volume: -
Issue: 9
Pages: 3129-3138
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Prognostic Significance of PD-1, PD-L1 and CD8 Gene Expression Levels in Gastric Cancer.2020
Author(s)
Ito S, Masuda T, Noda M, Hu Q, Shimizu D, Kuroda Y, Eguchi H, Tobo T, Utsunomiya T, Mimori K.
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Journal Title
Oncology.
Volume: 98(7)
Issue: 7
Pages: 501-511
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] SF3B4 Plays an Oncogenic Role in Esophageal Squamous Cell Carcinoma.2020
Author(s)
Kidogami S, Iguchi T, Sato K, Yoshikawa Y, Hu Q, Nambara S, Komatsu H, Ueda M, Kuroda Y, Masuda T, Mori M, Doki Y, Mimori K.
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Journal Title
Anticancer Res.
Volume: 40(5)
Issue: 5
Pages: 2941-2946
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] KIF15 Expression in Tumor-associated Monocytes Is a Prognostic Biomarker in Hepatocellular Carcinoma.2020
Author(s)
Kitagawa A, Masuda T, Takahashi J, Tobo T, Noda M, Kuroda Y, Hu Q, Kouyama Y, Kobayashi Y, Kuramitsu S, Sato K, Fujii A, Yoshikawa Y, Wakiyama H, Shimizu D, Tsuruda Y, Eguchi H, Doki Y, Mori M, Mimori K.
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Journal Title
Cancer Genomics Proteomics.
Volume: 17(2)
Issue: 2
Pages: 141-149
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Endogenous YAP1 activation drives immediate onset of cervical carcinoma in situ in mice.2020
Author(s)
Miki Nishio , Yoko To , Tomohiko Maehama , Yukari Aono , Junji Otani , Hiroki Hikasa , Akihiro Kitagawa , Koshi Mimori , Takehiko Sasaki , Hiroshi Nishina , Shinya Toyokuni , John P Lydon , Kazuwa Nakao , Tak Wah Mak , Tohru Kiyono , Hidetaka Katabuchi , Hironori Tashiro , Akira Suzuki
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Journal Title
Cancer science
Volume: 111
Issue: 10
Pages: 3576-3578
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] GTF2IRD1 on chromosome 7 is a novel oncogene regulating the tumor-suppressor gene TGFβR2 in colorectal cancer.2020
Author(s)
Nambara S, Masuda T, Kobayashi Y, Sato K, Tobo T, Koike K, Noda M, Ogawa Y, Kuroda Y, Ito S, Eguchi H, Sugimachi K, Mimori K.
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Journal Title
Cancer Sci.
Volume: 111(2)
Issue: 2
Pages: 343-355
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Reduction of T-Box 15 gene expression in tumor tissue is a prognostic biomarker for patients with hepatocellular carcinoma2020
Author(s)
Yuji Morine, Tohru Utsunomiya, Yu Saito, Shinichiro Yamada, Satoru Imura, Tetsuya Ikemoto, Akihiro Kitagawa, Yuta Kobayashi, Seiichiro Takao, Keisuke Kosai, Koshi Mimori, Yasuhito Tanaka, Mitsuo Shimada
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Journal Title
Oncotarget
Volume: 11
Issue: 52
Pages: 4803-4812
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Presentation] これからの散発性大腸がんに対するICB免疫療法の適応に関する提案2020
Author(s)
斉藤秀幸,増田隆明,倉光正太郎,八代正和,高尾誠一朗,小齊啓祐,小林雄太,本村有史,小池健輔,高橋純一,大津甫,武石一樹,米村祐輔,佐伯浩司,三森功士
Organizer
第79回日本癌学会学術総会
Related Report
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