Elucidation of molecular mechanisms underlying colon carcinogenesis and discovery of therapeutic targets by using a novel in vitro model

2016 Fiscal Year Final Research Report

• Project/Area Number: 26290044
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Hippo Yoshitaka 千葉県がんセンター(研究所), 発がん制御研究部, 部長 (30359632)
• Co-Investigator(Kenkyū-buntansha): 落合 雅子 国立研究開発法人国立がん研究センター, その他部局等, 研究員 (90150200)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 発がん / 大腸がん / オルガノイド / ３次元培養

Outline of Final Research Achievements

We have previously demonstrated that multi-step intestinal tumorigenesis can be recapitulated by lentivirally introducing genetic aberrations into murine intesitnal organoids. By using this cell-based model, we aimed at elucidation of molecular mechanisms underlying colon carcinogenesis. Specifically, we isolated small intestines from conditional knockout or knock-in mice for Apc and mutant Kras, respectively, and transduced organoids with Cre-recombinase to achieve in vitro recombination. We investigated if RNAi-mediated inactivation of genes frequently mutated in colon cancer could cooperate towards tumorigenesis with Apc loss or Kras activation, by inoculating transduced oragnoids in dorsal skin of immunodeficient mice, and gained new insights into impacts of these genes. We also administered food-borne carcinogens to organoids, to see environmental factors could indeed affect tumorigenesis. These observations would likely highlight the relevance of this new model.

Free Research Field

分子腫瘍学