Establishment of mouse models and organoids corresponding to colorectal cancer molecular subtypes and their clinical application

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08694
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Hiroshima University (2019-2020); Department of Clinical Research, National Hospital Organization Kure Medical Center (2018)
• Principal Investigator: Hinoi Takao 広島大学, 病院(医), 特任教授 (10444689)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 大腸癌のマウスモデル / 大腸癌のサブタイプ分類 / 分子腫瘍学 / FAP / RASシグナル伝達

Outline of Final Research Achievements

Consensus molecular subtypes(CMS) is the new colorectal cancer classification system based on gene expression profiles. Previously, we generated CMS1 mouse model characterized by MSI-high and CMS2 model characterized by CIN phenotype. In this study we generated GEMMs which recapitulate CMS3 (the metabolic phenotype) model characterized by the dysregulation of metabolic pathways with the activation of KRAS pathway and CMS4(mesenchymal subtype) model. In CMS3 model, we studied colonic neoplasia that has KrasG122V/BrafV600E mutation with Apc inactivation and compared gene expression profiles among Kras/Braf WT, Kras-mutated, and Braf-mutated mouse colon tumors to seek new molecular targets corresponding to the KRAS-BRAF-MAPK axis. We found Greb1 was the most upregulated gene in Braf-mutated tumors, suggesting the potential target of Wnt and RAS signaling pathway. We also established GEMM mouse with CMS4 subtypes and organoids, indicating the phenotype of CMS4 with promoted carcinogenesis.

Free Research Field

消化器癌の分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

大腸癌は罹患数が最も多い癌であり女性の癌死亡の第１位であり対策が急務である。大腸癌の臨床像や治療法を４つ亜型（サブタイプ）に分類したMolecular Consensus Subtype（MCS）の1-4型が欧米でも採用されつつある。私共は各CMS分類を再現する新規大腸癌マウスモデルを作製しており、これまでCMS1とCMS2を確立した。本研究では、治療抵抗性のCMS3とCMS4モデルを確立した。CMS3モデルではGreb1が新規治療標的として同定された。CMS4モデルでも、腫瘍の特性や治療法の検索が可能となった。これらのマウスモデルは大腸癌の基礎研究や新規治療法の探索に有用と思われる。