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Analysis of acquisition of metastasis property by p53 LOH and heterogeneity of tumor cells in CRC mouse model

Research Project

Project/Area Number 17K07162
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionKanazawa University

Principal Investigator

Nakayama Mizuho  金沢大学, がん進展制御研究所, 助教 (20398225)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords大腸がん / 悪性化 / p53 LOH / 転移 / p53 / Loss of heterogeneity / マウスモデル
Outline of Final Research Achievements

The accumulation of driver gene mutations causes colorectal cancer (CRC). However, it still unknown that which gene is responsible for metastasis. Previously, we generated CRC mouse model which carries four driver gene mutations (Apc, Kras, Tgfbr2, p53; AKTP) and established the organoids from mouse tumor.
This project focused p53 which is the most frequently mutated gene in pan-cancer cohort. We found that LOH of wild type-p53 with mutation cells (AKTPLOH/M), that p53 status is frequently seen in human malignant tumor, are enriched in metastasis legions when AKTP+/M organoids are injected in mouse spleen. Moreover, p53 LOH is required for the dormant cell survival and clonal expansion abilities. RNA seq. analyses revealed that inflammatory and growth factor/MAPK pathways are activated in AKTPLOH/M cells, while the stem cell signature is upregulated in both AKTPNull and AKTPLOH/M cells, indicating p53 LOH promotes mutant p53 driven metastasis through a distinct pathway activation.

Academic Significance and Societal Importance of the Research Achievements

大腸がんの転移に関わる原因遺伝子はわかっていない。本研究は多くのがんで変異が入っているp53に着目し、大腸がん転移前後のp53遺伝子とそれに伴う腫瘍細胞の悪性形質を調べた。p53に変異が入っただけでは悪性度は低いが、これに野生型p53欠損(LOH)が組み合わさることで、高い転移能力を獲得していることが分かった。ヒトのがんで見つかるp53の多くが変異+LOHの組み合わせであることから、このようなp53は転移における責任遺伝子のひとつであることが示唆された。この研究によりp53変異によるがん悪性化の詳細なメカニズムが明らかとなり、また創薬の分野においてもp53はターゲットとして広がりが期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (10 results)

All 2020 2019 2018 2017

All Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (5 results) (of which Invited: 2 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties2020

    • Author(s)
      Mizuho Nakayama, Chang Pyo Hong, Hiroko Oshima, Eri Sakai, Seong-Jin Kim, Masanobu Oshima
    • Journal Title

      Nature Communications

      Volume: -

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer.2018

    • Author(s)
      Sakai E, Nakayama M, Oshima H, Kouyama Y, Niida A, Fujii S, Ochiai A, Nakayama KI, Minori K, Suzuki Y, Hong CP, Ock CY, Kim SJ, Oshima M.
    • Journal Title

      Cancer Res.

      Volume: 78 Issue: 5 Pages: 1334-1346

    • DOI

      10.1158/0008-5472.can-17-3303

    • NAID

      120006452378

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation.2017

    • Author(s)
      Nakayama M, Sakai K, Echizen K, Yamada Y, Oshima H, Han TS, Ohki R, Fujii S, Ochiai A, Robine S, Voon DC, Tanaka T, Taketo MM, Oshima M.
    • Journal Title

      Oncogene

      Volume: 36 Issue: 42 Pages: 5885-5896

    • DOI

      10.1038/onc.2017.194

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 変異型p53における野生型p53 欠失によるp53-Loss of heterogeneityは、潜在性がんとしての性質を亢進する2019

    • Author(s)
      Mizuho Nakayama, Eri Sakai, Hiroko Oshima, Seong-Jin Kim, Masanobu Oshima
    • Organizer
      第78回日本がん学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] がん悪性化モデルマウスとオルガノイドを使った解析ー変異型p53のがんにおける新規機能ー2019

    • Author(s)
      中山瑞穂
    • Organizer
      大阪大学蛋白質研究所セミナー「がん研究の新機軸」
    • Related Report
      2019 Annual Research Report
  • [Presentation] Combination of gain-of-function muttaion and lost of wild-type allele in p53 promotes colon cancer tumorigenicity.2018

    • Author(s)
      Nakayama M, Sakai E, Suzuki Y, Oshima H, Oshima M.
    • Organizer
      第77回日本がん学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Novel model systems for colon cancer progression by accumulation of multiple driver mutations2017

    • Author(s)
      Mizuho Nakayama, Eri Sakai, Hiroko Oshima, Kanae Echizen, Satoshi Fujii, Atsusi Ochiai, Keiichi I. Nakayama, Masanobu Oshima
    • Organizer
      第76回日本がん学会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Colon cancer malignant progression by mutant p53 through hyper-activation of Wnt signaling and induction of inflammatory pathway2017

    • Author(s)
      Masanobu Oshima, Mizuho Nakayama, Eri Sakai
    • Organizer
      第40回分子生物学会年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Patent(Industrial Property Rights)] オルガノイド及びその利用2017

    • Inventor(s)
      大島正伸、中山瑞穂、坂井絵梨
    • Industrial Property Rights Holder
      大島正伸、中山瑞穂、坂井絵梨
    • Industrial Property Rights Type
      特許
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report
    • Overseas

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Published: 2017-04-28   Modified: 2021-02-19  

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