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Genetic- and Somatic-regualtion of colorectal cancer

Research Project

Project/Area Number 18H02684
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

YAO Ryoji  公益財団法人がん研究会, がん研究所 細胞生物部, 部長 (80291095)

Co-Investigator(Kenkyū-buntansha) 足立 淳  国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 創薬デザイン研究センター, プロジェクトリーダー (20437255)
長山 聡  公益財団法人がん研究会, 有明病院 消化器外科, 医長 (70362499)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Keywords患者由来オルガノイド / 大腸がん / KRAS / IFN/STATシグナル / MEK阻害剤 / 家族性大腸腺腫症 / 遺伝学的背景 / 遺伝的背景 / 体細胞変異
Outline of Final Research Achievements

Familial adenomatous polyposis coli (FAP) is an autosomal-dominant inherited disease caused by ger- mline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP). In this study, we established 42 organoids from three CFAP patients and two AFAP patients. Comprehensive gene expression analysis demonstrated a close association between IFN/STAT signaling and the phenotypic features of FAP patients. Genetic disruption of Stat1 in the mouse model of FAP reduced tumor formation. We found that enhanced IFN/STAT signaling in CFAP conferred resistance to MEK inhibitors. These findings reveal the crosstalk between RAS signaling and IFN/ STAT signaling, which contributes to the tumor-forming potential and drug response. These results offer a rationale for targeting of IFN/STAT signaling and for the strati- fication of CRC patients.

Academic Significance and Societal Importance of the Research Achievements

大腸がんは、遺伝子変異の蓄積により進展することが知られており、診断や治療法の選択の指標となっている。しかし、同一の遺伝子変異を持っていても転帰や化学療法の奏功率には、個人差がある。本研究では、遺伝的に多数の腫瘍を発生する家族性大腸腺腫症患者に生じた腫瘍からオルガノイドを樹立し、造腫瘍性と分子標的治療薬に対する感受性を検討した。その結果、遺伝的にIFN/STATシグナルが高い患者に生じた腫瘍は、造腫瘍性が高く、化学療法に対して抵抗性を示すことが明らかになった。

Report

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

    (21 results)

All 2021 2020 2019 2018

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (15 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer2021

    • Author(s)
      Okamoto Takuya、duVerle David、Yaginuma Katsuyuki、Natsume Yasuko、Yamanaka Hitomi、Kusama Daisuke、Fukuda Mayuko、Yamamoto Mayuko、Perraudeau Fanny、Srivastava Upasna、Kashima Yukie、Suzuki Ayako、Kuze Yuuta、Takahashi Yu、Ueno Masashi、Sakai Yoshiharu、Noda Tetsuo、Tsuda Koji、Suzuki Yutaka,Nagayama Satoshi,Yao Ryoji
    • Journal Title

      Stem Cell Reports

      Volume: 16 Issue: 4 Pages: 954-967

    • DOI

      10.1016/j.stemcr.2021.02.012

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evaluation of the RAS signaling network in response to MEK inhibition using organoids derived from a familial adenomatous polyposis patient2020

    • Author(s)
      Osumi Hiroki、Muroi Atsushi、Sakahara Mizuho、Kawachi Hiroshi、Okamoto Takuya、Natsume Yasuko、Yamanaka Hitomi、Takano Hiroshi、Kusama Daisuke、Shinozaki Eiji、Ooki Akira、Yamaguchi Kensei、Ueno Masashi、Takeuchi Kengo、Noda Tetsuo、Nagayama Satoshi、Koshikawa Naohiko、Yao Ryoji
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 17455-17455

    • DOI

      10.1038/s41598-020-74530-x

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] IFN/STAT signaling controls tumorigenesis and the drug response in colorectal cancer2019

    • Author(s)
      Sakahara Mizuho、Okamoto Takuya、Oyanagi Jun、Takano Hiroshi、Natsume Yasuko、Yamanaka Hitomi、Kusama Daisuke、Fusejima Mishio、Tanaka Norio、Mori Seiich、Kawachi Hiroshi、Ueno Masashi、Sakai Yoshiharu、Noda Tetsuo、Nagayama Satoshi、Yao Ryoji
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 4 Pages: 1293-1305

    • DOI

      10.1111/cas.13964

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MCRIP1 promotes the expression of lung-surfactant proteins in mice by disrupting CtBP-mediated epigenetic gene silencing2019

    • Author(s)
      Weng Jane S.、Nakamura Takanori、Moriizumi Hisashi、Takano Hiroshi、Yao Ryoji、Takekawa Mutsuhiro
    • Journal Title

      Communications Biology

      Volume: 2 Issue: 1 Pages: 227-227

    • DOI

      10.1038/s42003-019-0478-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Odf2 haploinsufficiency causes a new type of decapitated and decaudated spermatozoa, Odf2-DDS, in mice2019

    • Author(s)
      Ito C, Akutsu H, Yao R, Yoshida K, Yamatoya K, Mutoh T, Makino T, Aoyama K, Ishikawa H, Kunimoto K, Tsukita S, Noda T, Kikkawa M, Toshimori K.
    • Journal Title

      Sci Rep.

      Volume: 9 Issue: 1 Pages: 14249-14249

    • DOI

      10.1038/s41598-019-50516-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Improved phosphoproteomic analysis for phosphosignaling and active-kinome profiling in Matrigel-embedded spheroids and patient-derived organoids2018

    • Author(s)
      Abe Yuichi、Tada Asa、Isoyama Junko、Nagayama Satoshi、Yao Ryoji、Adachi Jun、Tomonaga Takeshi
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 11401-11401

    • DOI

      10.1038/s41598-018-29837-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 患者由来オルガノイドを用いた大腸がん組織の細胞不均一性の解明2021

    • Author(s)
      八尾 良司
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] がん患者由来オルガノイドを用いた研究2020

    • Author(s)
      八尾 良司
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] ヒト大腸がんオルガノイド同所移植マウスモデルにおける転移腫瘍の発生とEMTマーカーの発現2020

    • Author(s)
      柳沼 克幸、岡本 拓也、長山 聡、八尾 良司
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 患者由来大腸がんオルガノイド同所移植マウスモデルにおける転移播種細胞の同定2020

    • Author(s)
      岡本 拓也、柳沼 克幸、長山 聡、八尾 良司
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 大腸癌組織を構成する細胞集団の多様性2020

    • Author(s)
      長山 聡、岡本 拓也、八尾 良司
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 患者由来オルガノイドを用いた大腸がんの発生、転移・再発機構の解明2020

    • Author(s)
      八尾 良司
    • Organizer
      患者由来がんモデル講演会 -基礎研究から臨床応用まで-
    • Related Report
      2020 Annual Research Report
  • [Presentation] Comparative analysis of patient-derived organoids from primary colorectal cancer and matched metastatic and recurrent lesions.2019

    • Author(s)
      八尾 良司
    • Organizer
      Cell Symposium: Engineering Organoids and Organs
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 進行大腸がんオルガノイドの1細胞解析2019

    • Author(s)
      八尾 良司、長山 聡、鈴木 穰
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 大腸がん同所移植モデルマウスを用いた転移の再現2019

    • Author(s)
      岡本 拓也、柳沼 克幸、長山 聡、八尾 良司
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 大腸癌発生と薬剤感受性におけるIFN/STATシグナル伝達系の関与2019

    • Author(s)
      長山 聡、岡本 拓也、八尾 良司
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 大腸がん組織を構成する細胞集団の多様性と階層性2019

    • Author(s)
      八尾 良司
    • Organizer
      第1回鹿児島がんと代謝セミナー
    • Related Report
      2018 Annual Research Report
  • [Presentation] IFN/STAT signaling controls tumorigenesis of colorectal cancers2019

    • Author(s)
      八尾 良司
    • Organizer
      11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
    • Related Report
      2018 Annual Research Report
  • [Presentation] Mouse model of metastatic colorectal cancer by orthotopic transplantation of patient derived organoids2019

    • Author(s)
      岡本 拓也
    • Organizer
      AACR Annual Meeting 2019
    • Related Report
      2018 Annual Research Report
  • [Presentation] 体細胞変異と遺伝的背景による大腸がん薬剤感受性制御機構2018

    • Author(s)
      八尾 良司
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 患者由来大腸がんオルガノイドを用いた転移モデルマウス2018

    • Author(s)
      岡本 拓也
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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