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Mechanism of heterogeneity-induced colon cancer malignant progression

Research Project

Project/Area Number 18H04030
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionKanazawa University

Principal Investigator

OSHIMA Masanobu  金沢大学, がん進展制御研究所, 教授 (40324610)

Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥44,070,000 (Direct Cost: ¥33,900,000、Indirect Cost: ¥10,170,000)
Fiscal Year 2021: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2020: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Fiscal Year 2019: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Fiscal Year 2018: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Keywords大腸がん / オルガノイド / 多段階発がん / ポリクローナル転移 / 遺伝的多様性 / 転移 / ナノ計測 / 多様性 / マウスモデル / 上皮間葉転換 / 悪性化進展 / ドライバー遺伝子変異
Outline of Final Research Achievements

In this project, we have examined the role of genetic heterogeneity in malignant progression of intestinal tumors. For this purpose, we have constructed genetically engineered mouse models and tumor-derived organoid transplantation models. By comprehensive histological analysis, we have successfully linked specific combinations of driver mutations to each process of malignant progression, such as submucosal invasion, intravasation, and metastasis. Moreover, we found that malignant metastatic tumor cells induce fibrotic niche generation in the liver by activation of hepatic stellate cells, and non-metastatic cells survive and proliferate in the fibrotic microenvironment, which leads to development of polyclonal metastasis. These results suggest that targeting fibrotic niche generation in the liver will be a possible preventive and therapeutic strategy against colon cancer metastasis.

Academic Significance and Societal Importance of the Research Achievements

がんによる死亡原因の多くは転移再発が占めており、その克服のためにも悪性化および転移機構の理解は重要な研究課題である。これまでに、遺伝子変異の蓄積が悪性化を誘導する「多段階発がん」の概念が樹立している一方で、がん組織における遺伝的多様性が悪性化に関与することも指摘されている。本研究成果は、遺伝学的解析により、粘膜下浸潤や転移等の悪性化を誘導するp53遺伝子を含むドライバー遺伝子変異の関与を明らかにして、多段階発がん機構の理解を広げた。さらに、遺伝的多様ながん細胞集団によるポリクローナル転移機構を個体レベルで明らかにしたことで、新たながん転移機構の概念の樹立に貢献した。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (43 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (3 results) Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 12 results) Presentation (21 results) (of which Int'l Joint Research: 5 results,  Invited: 17 results) Book (2 results) Remarks (4 results)

  • [Int'l Joint Research] ソウル国立大学(韓国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Seoul National University(韓国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Seoul National University(韓国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Nano-scale physical properties characteristic to intestinal cancer cells identified by high speed-scanning ion conductance microscope2022

    • Author(s)
      D. Wang, L. Sun, S. Okuda, D. Yamamoto, M. Nakayama, H. Oshima, H. Saito, Y. Kouyama, K. Mimori, T. Ando, S. Watanabe, M. Oshima
    • Journal Title

      Biomaterials

      Volume: 280 Pages: 121256-121256

    • DOI

      10.1016/j.biomaterials.2021.121256

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Characterization of RNF43 frameshift mutations that drive Wnt ligand‐ and R‐spondin‐dependent colon cancer2022

    • Author(s)
      Yamamoto Daisuke、Oshima Hiroko、Wang Dong、Takeda Haruna、Kita Kenji、Lei Xuelian、Nakayama Mizuho、Murakami Kazuhiro、Ohama Takashi、Takemura Hirofumi、Toyota Mutsumi、Suzuki Hiromu、Inaki Noriyuki、Oshima Masanobu
    • Journal Title

      The Journal of Pathology

      Volume: 257 Issue: 1 Pages: 39-52

    • DOI

      10.1002/path.5868

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stem Cells, Helicobacter pylori, and Mutational Landscape: Utility of Preclinical Models to Understand Carcinogenesis and to Direct Management of Gastric Cancer2022

    • Author(s)
      Liabeuf Dylan、Oshima Masanobu、Stange Daniel E.、Sigal Michael
    • Journal Title

      Gastroenterology

      Volume: 162 Issue: 4 Pages: 1067-1087

    • DOI

      10.1053/j.gastro.2021.12.252

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Genetic Alterations and Microenvironment that Drive Malignant Progression of Colorectal Cancer: Lessons from Mouse and Organoid Models2022

    • Author(s)
      Nakayama Mizuho、Wang Dong、Kok Sau Yee、Oshima Hiroko、Oshima Masanobu
    • Journal Title

      Journal of Cancer Prevention

      Volume: 27 Issue: 1 Pages: 1-6

    • DOI

      10.15430/jcp.2022.27.1.1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] FOXO3 is a latent tumor suppressor for FOXO3-positive and cytoplasmic-type gastric cancer cells2021

    • Author(s)
      Tsuji Toshikatsu、Maeda Yusuke、Kita Kenji、Murakami Kazuhiro、Saya Hideyuki、Takemura Hirofumi、Inaki Noriyuki、Oshima Masanobu、Oshima Hiroko
    • Journal Title

      Oncogene

      Volume: 40 Issue: 17 Pages: 3072-3086

    • DOI

      10.1038/s41388-021-01757-x

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Malignant subclone drives metastasis of genetically and phenotypically heterogenous cell clusters through fibrotic niche generation2021

    • Author(s)
      Kok Sau Yee、Oshima Hiroko、Takahashi Kei、Nakayama Mizuho、Murakami Kazuhiro、Ueda Hiroki R.、Miyazono Kohei、Oshima Masanobu
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 863-863

    • DOI

      10.1038/s41467-021-21160-0

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties2020

    • Author(s)
      Nakayama M, Hong CP, Oshima H, Sakai E, Kim SJ, and Oshima M.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 2333-2333

    • DOI

      10.1038/s41467-020-16245-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NF-kB activation promotes gastric tumorigenesis through the expansion of SOX2-positive epithelial cells.2019

    • Author(s)
      Echizen K, Horiuchi K, Aoki Y, Yamada Y, Minamoto T, Oshima H, and Oshima M.
    • Journal Title

      Oncogene

      Volume: accepted Issue: 22 Pages: 4250-4263

    • DOI

      10.1038/s41388-019-0702-0

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CRISPR-Cas9 mediated gene knockout in intestinal tumor organoids provides functional validation for colorectal cancer driver genes.2019

    • Author(s)
      Takeda H, Kataoka S, Nakayama M, Ali MAE, Oshima H, Yamamoto D, Park JW, Takegami Y, An T, Jenkins NA, Copeland NG, and Oshima M.
    • Journal Title

      Proc Natl Acad Sci USA

      Volume: 116 Issue: 31 Pages: 15635-15644

    • DOI

      10.1073/pnas.1904714116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] p53 mutation in colon cancer.2019

    • Author(s)
      Nakayama M and Oshima M.
    • Journal Title

      J Mol Cell Biol,

      Volume: Epub. ahead of print Issue: 4 Pages: 1-10

    • DOI

      10.1093/jmcb/mjy075

    • NAID

      120006605142

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice.2018

    • Author(s)
      Han TS, Voon DC, Oshima H, Nakayama M, Echizen K, Sakai E, Yong ZWE, Murakami K, Yu L, Minamoto T, Ock CY, Jenkins BJ, Kim SJ, Yang HK, Oshima M
    • Journal Title

      Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice

      Volume: 156 Issue: 4 Pages: 1140-1155

    • DOI

      10.1053/j.gastro.2018.11.059

    • NAID

      120006621945

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.2018

    • Author(s)
      Oshima H, Kok SY, Nakayama M, Murakami K, Voon DC, Kimura T, Oshima M
    • Journal Title

      FASEB J.

      Volume: 33 Issue: 2 Pages: 1873-1886

    • DOI

      10.1096/fj.201801176r

    • NAID

      120006621946

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion.2018

    • Author(s)
      Echizen K, Oshima H, Nakayama M, Oshima M
    • Journal Title

      Advances in Biological Regulation

      Volume: 印刷中 Pages: 39-45

    • DOI

      10.1016/j.jbior.2018.02.001

    • NAID

      120006473980

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 個体モデルの観察による大腸がん悪性化過程の解析2022

    • Author(s)
      大島正伸
    • Organizer
      令和3年度 先端モデル動物支援プラットフォーム成果発表会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Malignant cancer cells drive polyclonal metastasis through fibrotic niche generation.2021

    • Author(s)
      Masanobu Oshima
    • Organizer
      第39回 札幌国際がんシンポジウム
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] がん微小環境ネットワークを制御するシグナルを標的とした治療法の開発2021

    • Author(s)
      大島正伸、中山瑞穂、大島浩子
    • Organizer
      第42回 日本炎症・再生医学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Gastric cancer mouse model: inflammation, genetic alteration, and impaired differentiation2021

    • Author(s)
      Masanobu Oshima
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Gain-of-function mutant p53 hyperactivates Wnt signaling in colon cancer cells2021

    • Author(s)
      Mizuho Nakayama、Hiroko Oshima、Masanobu Oshima
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] The fibrotic microenvironment that promotes polyclonal metastasis of intestinal tumors2021

    • Author(s)
      Hiroko Oshima、Mizuho Nakayama、Kei Takahashi、Kohei Miyazono、Masanobu oshima
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Tumor-derived organoids to study gastrointestinal cancer metastasis2021

    • Author(s)
      Masanobu Oshima
    • Organizer
      第80回 日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 炎症とがん転移2020

    • Author(s)
      大島正伸
    • Organizer
      第41回日本炎症・再生医学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 大腸がんの悪性化進展における炎症性バイオマーカー2020

    • Author(s)
      大島正伸,中山瑞穂,Dong Wang,大島浩子,渡辺信嗣
    • Organizer
      第40回日本分子腫瘍マーカー研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] How genetic alterations promote malignant progression of colon cancer?2020

    • Author(s)
      Oshima M.
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Gain-of-function mutation of p53 for malignant progression of cancer2020

    • Author(s)
      Oshima M.
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] p53-loss of heterozygosity with p53 gain-of-function mutation leads to cancer dormancy of intestinal tumors.2019

    • Author(s)
      Nakayama M, Sakai E, Oshima H, Tan P, Oshima M.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Mechanism for intestinal tumor metastasis by polyclonal origins.2019

    • Author(s)
      Sau Yee Kok, Oshima H, Sakai E, Nakayama M, Oshima M.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Regulation of Foxo3a localization in gastric cancer cells.2019

    • Author(s)
      Oshima H, Maeda Y, Tsuji T, Oshima M.
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Biological mechanism of polyclonal metastasis of colorectal cancer.2019

    • Author(s)
      Oshima M.
    • Organizer
      50th Commemorative International Symposium of the Princess Takamatsu Cancer Research Fund
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Multistep tumorigenesis and polyclonal metastasis of colon cancer.2019

    • Author(s)
      Oshima M.
    • Organizer
      24th Annual Meeting of the Korean Society of Cancer Prevention (KSCP)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 遺伝学的アプローチによる大腸がん悪性化研究の新展開2019

    • Author(s)
      大島正伸
    • Organizer
      第1回日本遺伝学会春季分科会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Comprehensive phenotype characterization of colon cancer with various combination of driver mutations.2018

    • Author(s)
      Oshima M.
    • Organizer
      9th General Assembly and International Conference of Asian Pacific Organization for Cancer Prevention (APOCP)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Combined driver mutations for malignant progression of intestinal tumorigenesis.2018

    • Author(s)
      Oshima M.
    • Organizer
      37th Sapporo International Cancer Symposium
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 多重ドライバー変異による大腸がん悪性化モデル研究2018

    • Author(s)
      大島正伸
    • Organizer
      第65回日本実験動物学会総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Inflammatory microenvironment for malignant progression of colon cancer.2018

    • Author(s)
      Oshima M, Nakayama M, Oshima H.
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Book] Research and Clinical Applications of Targeting Gastric Neoplasms, Ed by Brendan Jenkins2021

    • Author(s)
      Hiroko Oshima、Xiaoli Ju、Kanae Echizen、Tae-Su Han、Masanobu Oshima
    • Total Pages
      16
    • Publisher
      Elsevier
    • ISBN
      9780323855631
    • Related Report
      2021 Annual Research Report
  • [Book] Methods in Molecular Biology, Inflammation and Cancer2018

    • Author(s)
      Han TS, Oshima M.
    • Total Pages
      12
    • Publisher
      Springer
    • ISBN
      9781493975679
    • Related Report
      2018 Annual Research Report
  • [Remarks] 金沢大学がん進展制御研究所腫瘍遺伝学研究分野HP

    • URL

      http://genetics.w3.kanazawa-u.ac.jp

    • Related Report
      2021 Annual Research Report
  • [Remarks] 金沢大学ナノ生命科学研究所

    • URL

      https://nanolsi.kanazawa-u.ac.jp/en/gut-feeling-visualizing-intestinal-tumors/

    • Related Report
      2021 Annual Research Report
  • [Remarks] 金沢大学がん進展制御研究所 腫瘍遺伝学研究分野

    • URL

      http://genetics.w3.kanazawa-u.ac.jp

    • Related Report
      2020 Annual Research Report 2018 Annual Research Report
  • [Remarks] 金沢大学がん進展制御研究所腫瘍遺伝学研究分野 HP

    • URL

      http://genetics.w3.kanazawa-u.ac.jp

    • Related Report
      2019 Annual Research Report

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Published: 2018-04-23   Modified: 2023-01-30  

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