Sleeping Beauty Transposon mutagenesis screen for identifying driver genes in uterine leiomyosarcoma

• Project/Area Number: 17K11277
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka University
• Principal Investigator: Kodama Michiko 大阪大学, 医学系研究科, 助教 (70791391)
• Co-Investigator(Kenkyū-buntansha): 澤田 健二郎 大阪大学, 医学系研究科, 講師 (00452392) ; 馬淵 誠士 奈良県立医科大学, 医学部, 講師 (00452441) ; 橋本 香映 大阪大学, 医学系研究科, 助教 (90612078)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: トランスポゾン / スクリーニング / 子宮平滑筋肉腫 / Sleeping beautyトランスポゾン / フォワードジェネティックスクリーニング / ドライバー遺伝子

Outline of Final Research Achievements

Uterine leiomyosarcoma is a rare malignant tumor with extremely high aggressiveness. There are no standard treatments because the mechanism of its onset and metastasis have not been clarified. We identified several candidate genes involved in sarcomagenesis and hematogenous lung metastasis from a novel mouse model that developed uterine leiomyosarcoma by SB transposon insertional mutagenesis. Using human uterine leiomyosarcoma cell lines, it was confirmed that cell proliferation was suppressed, migration was reduced, and stemness was suppressed by inhibiting candidate genes. In addition, it was confirmed that the candidate gene was highly expressed in primary and metastatic tissues of human uterine leiomyosarcoma. The gene involved in the development and progression of mouse uterine leiomyosarcoma identified by SB transposon screening was shown to be a therapeutic target also in human leiomyosarcoma.

Academic Significance and Societal Importance of the Research Achievements

非常に悪性度が高い希少悪性腫瘍である子宮平滑筋肉腫に対する治療は確立されておらず、予後不良な疾患であり、新たな治療戦略の発見が望まれている。本研究によって得られた成果は、子宮平滑筋肉腫に対する新たな治療標的を示し、予後の改善に繋がる可能性がある。
希少疾患であることから本疾患のみからなる大規模な遺伝子プロファイルデータセットは存在せず、また将来的にも困難であると予想され、発症・増悪に関与する遺伝子異常の同定は極めて難しい。その点でもSBトランスポゾンによるフォワードジェネティクス手法が非常に効果的に機能した、有意義な研究となった。

Research Products

• [Presentation] Sleeping beauty transposon mutagenesis screen identified cancer genes driving sarcomagenesis and metastases of uterine leiomyosarcoma (2019)
  • Author(s): 小玉美智子 中江彩 吉原弘祐 橋本香映 澤田健二郎 木村正
  • Organizer: 第61回日本婦人科腫瘍学会
• [Presentation] 平滑筋肉腫の新しい動物モデルを用いたゲノム解析 (2019)
  • Author(s): 小玉美智子
  • Organizer: 第4回日本肉腫学会
• [Presentation] Sleeping Beauty transposon mutagenesis screen identifies cancer genes of uterine leiomyosarcoma driving sarcomagenesis and lung metastasis. (2018)
  • Author(s): Michiko Kodama, Takahiro Kodama, Justin Y. Newberg, Jean C. Tien, Roberto Rangel, Aya Nakae, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Nancy A. Jenkins, Neal G. Copeland.
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Sleeping beauty transposon insertional mutagenesis identified driver genes of uterine leiomyosarcoma. (2018)
  • Author(s): Michiko Kodama, Hiroko Shimura, Aya Nakae, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura.
  • Organizer: The 17th Biennial Meeting of the International Gynecologic Cancer Society (International Gynecologic Cancer Society)
  • Int'l Joint Research
• [Presentation] トランスポゾンを用いたマウス子宮平滑筋肉腫発症に関与するドライバー遺伝子のスクリーニング (2018)
  • Author(s): 小玉美智子 中江彩 志村寛子 橋本香映 馬淵誠士 澤田健二郎 木村正
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Sleeping Beauty transposon insertional mutagenesis screen of uterine leiomyosarcoma identified cancer genes driving sarcomagenesis. (2018)
  • Author(s): Michiko Kodama, Takahiro Kodama, Justin Y. Newberg, Jean C. Tien, Roberto Rangel, Aya Nakae, Tadashi Kimura, Neal G. Copeland, Nancy A. Jenkins.
  • Organizer: 11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
  • Int'l Joint Research