In vivo analysis of communications in tumor micro-environment constructed by tumor cells carrying gain-of-function p53 mutation and p53 null mutation in colorectal cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07585
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa University
• Principal Investigator: Nakayama Mizuho 金沢大学, がん進展制御研究所, 准教授 (20398225)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 変異p53 / 大腸がん / LOH

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 p53 mutant (R270H) cells (AKTP-LOH/R270H) are enriched in metastasis legions when AKTP+/R270H organoids are injected into 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/R270H cells, while the stem cell signature is upregulated in both AKTPNull and AKTPLOH/R270H cells, indicating p53 LOH promotes mutant p53 driven metastasis through a distinct pathway activation.

Free Research Field

腫瘍細胞生物学

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ミスセンス変異が入っている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にミスセンス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の多くがミスセンス変異＋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であることが示唆された。この結果はp53変異によるがん悪性化メカニズムの理解を深め、p53を標的とする創薬開発にも貢献するものである。