2023 Fiscal Year Final Research Report
Elucidation of genetic interactions underlying tumor development and metastasis using murine endometrial organoids
| Project/Area Number |
21K09506
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 56040:Obstetrics and gynecology-related
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| Research Institution | Chiba Cancer Center (Research Institute) |
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Principal Investigator |
Maru Yoshiaki 千葉県がんセンター(研究所), がん予防センター 精密腫瘍モデル研究室, 研究員 (30742754)
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| Co-Investigator(Kenkyū-buntansha) |
筆宝 義隆 千葉県がんセンター(研究所), 研究所, 研究所長 (30359632)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | 子宮体がん / 癌肉腫 / オルガノイド / 発がん / 転移 |
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| Outline of Final Research Achievements |
We reconstituted genetic aberrations in endometrial organoids (EmOR) from various genetically engineered mice by lentivirally introducing cDNA and shRNA, and examined their tumorigenicity by inoculation into dorsal skin of nude mice. We found that EmOR carrying mutant Kras and Cdkn2a knockdown or Trp53 loss developed carcinosarcoma. Unlike an earlier in vivo study, EmOR with mutant Kras and concomitant Pten knockdown never developed tumor, whereas late-passage EmOR exclusively gave rise to adenocarcinoma with lymph node metastasis. Through the analyses of the resultant tumor, we found that Tgfbr2 loss may be critically implicated in endometrial carcinogenesis. The validation experiments revealed that KrasG12D-expressing early-passage EmOR with Tgfbr2 loss indeed developed carcinoma, whereas additional knockdown of Cdkn2a or Pten almost invariably induced metastasis. Thus, we gained novel insights into the carcinogenesis and metastasis of endometrial cancer using organoid models.
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| Free Research Field |
分子腫瘍学
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| Academic Significance and Societal Importance of the Research Achievements |
子宮体がんの発がんおよび転移機構を解明するために、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マウス正常子宮内膜細胞を培養し、遺伝子異常の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。ヒト子宮体がんで高頻度の遺伝子異常やシグナル経路の異常をマウス子宮内膜オルガノイドに再現することで発がんだけでなく転移性腫瘍の誘導に成功した。本アプローチを利用することで、子宮体がんで同定された意義不明な遺伝子異常の発がんに与える影響の検証も可能となり、子宮体がんの本態解明や治療標的探索など様々な研究を促進することが期待される。
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