Genetic reconstitution of tumorigenesis of ovarian serous carcinoma using organoid-based approach

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16823
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Maru Yoshiaki 千葉県がんセンター(研究所), 発がん研究グループ 発がん制御研究部, 研究員 (30742754)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 卵巣がん / 漿液性癌 / オルガノイド / 発がん

Outline of Final Research Achievements

We reconstituted genetic aberrations by lentivirally introducing cDNA and shRNA into murine fallopian tube organoids from various genetically engineered mice and investigated tumorigenicity by inoculation of these transduced organoids into dorsal skin of nude mice. Although Trp53 is the most frequently mutated gene in ovarian high-grade serous carcinoma (HGSC), Trp53 deletion alone in fallopian tube organoids was not sufficient for tumorigenesis. Additional induction of the activation of the PI3K/RAS pathways, which is frequently observed in HGSC, led to development of subcutaneous tumors with various histological types. In contrast, concurrent deletion of Apc only resulted in development of cystic lesion, in line with rare activation of the WNT pathway in HGSC. In conclusion, we established ex vivo carcinogenesis models with murine fallopian tube organoids.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

卵巣がんの発がん機構を解明するため、一般的に利用される遺伝子改変マウスの作製とは異なる方法で発がんモデルの確立を試みた。具体的にはオルガノイド培養法で卵巣がんの起源のひとつである卵管細胞を培養し、遺伝子異常導入後に免疫不全マウスに移植、腫瘍原性の有無を評価した。ヒト卵巣がんで高頻度の遺伝子異常をマウス卵管オルガノイドに再現することで発がんに成功した。本成果により、卵巣がんで報告されている意義不明な遺伝子異常や他の組織型の遺伝子異常が卵管上皮の発がんに与える影響の検証が可能になる。また、得られた腫瘍を卵巣がんの診断・治療標的探索などに利用することで、橋渡し研究の推進に貢献することが期待される。