Oncogenic role of aberrant SWI/SNF chromatin remodeling complex in synovial sarcoma

• Project/Area Number: 17K10985
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Keio University
• Principal Investigator: Nakayama Robert 慶應義塾大学, 医学部(信濃町), 講師 (00365298)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 発がん / 遺伝子 / ゲノム / トランスレーショナル・リサーチ / 融合遺伝子 / SWI/SNF複合体 / 肉腫 / 滑膜肉腫 / 希少がん / AYA世代 / SWI/SNF / BAF / クロマチンリモデリング複合体 / SS18-SSX / 遺伝子発現制御 / 悪性軟部腫瘍 / 癌 / トランスレーショナルリサーチ

Outline of Final Research Achievements

Synovial sarcoma is one of the common malignant soft tissue sarcomas in adolescent and young adult patients. Nearly 100% of tumors contain the pathognomonic t(X;18)(p11.2;q11.2) chromosomal translocation that produces the hallmark SS18-SSX fusion protein. Given that SS18 is a dedicated subunit of SWI/SNF chromatin remodeling complexes, we hypothesized that malfunction of the aberrant SWI/SNF complexes that contain the SS18-SSX fusion should be responsible for the development of synovial sarcoma, and conducted biochemical analyses by knocking down the SS18-SSX gene in synovial sarcoma cell lines. Our study demonstrated that SS18-SSX globally hijacked BAF complexes on chromatin to activate a transcriptional signature specific to synovial sarcoma.

Academic Significance and Societal Importance of the Research Achievements

滑膜肉腫は思春期から若年成人に発生する代表的な悪性軟部腫瘍である。進行例に対する有効な治療法がないため、疾患特異的融合遺伝子SS18-SSXによる発がん機構を標的とした新規治療の開発に期待が高まっており、SS18-SSXの機能解析をおこなった本研究の成果はそれに向けた新規知見を提供した。さらに、本研究の成果は、SWI/SNF複合体の異常によって生じる様々な疾患における病態解明のモデルを提供した、という点で、非常に重要である。

Research Products

• [Int'l Joint Research] Dana-Farber Cancer Institute(米国)
• [Journal Article] Ten-year follow-up results of perioperative chemotherapy with doxorubicin and ifosfamide for high-grade soft-tissue sarcoma of the extremities: Japan Clinical Oncology Group study JCOG0304 (2019)
  • Author(s): Tanaka Kazuhiro、Mizusawa Junki、Naka Norifumi、Kawai Akira、et al.
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 1-7
  • DOI: 10.1186/s12885-019-6114-2
  • Peer Reviewed / Open Access
• [Journal Article] Pseudomyogenic hemangioendothelioma of bone treated with denosumab: a case report (2019)
  • Author(s): Otani Shinya、Nakayama Robert、Sekita Tetsuya、Hirozane Toru、Asano Naofumi、Nishimoto Kazumasa、Sasaki Aya、Okita Hajime、Morioka Hideo、Nakamura Masaya、Matsumoto Morio
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 872-872
  • DOI: 10.1186/s12885-019-6072-8
  • Open Access
• [Journal Article] The SS18-SSX Fusion Oncoprotein Hijacks BAF Complex Targeting and Function to Drive Synovial Sarcoma (2018)
  • Author(s): McBride Matthew J.、Pulice John L.、Beird Hannah C.、Ingram Davis R.、D’Avino Andrew R.、Shern Jack F.、Charville Gregory W.、Hornick Jason L.、Nakayama Robert T. et al.
  • Journal Title: Cancer Cell Volume: 33 Issue: 6 Pages: 1128-1141.e7
  • DOI: 10.1016/j.ccell.2018.05.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prospective comparison of various radiological response criteria and pathological response to preoperative chemotherapy and survival in operable high-grade soft tissue sarcomas in the Japan Clinical Oncology Group study JCOG0304 (2018)
  • Author(s): Tanaka K, Ogawa G, Mizusawa J, Naka N, Kawai A, Takahashi M, Hiruma T, Matsumoto Y, Tsuchiya H, Nakayama R, Hatano H, Emori M, Hosaka M, Yoshida Y, Toguchida J, Abe S, Asanuma K, Yokoyama R, Hiraga H, Yonemoto T, Morii T, Matsumoto S, Nagano A, Yoshikawa H, Fukuda H, Ozaki T, Iwamoto Y.
  • Journal Title: World Journal of Surgical Oncology Volume: 16 Issue: 1 Pages: 160-160
  • DOI: 10.1186/s12957-018-1462-y
  • Peer Reviewed
• [Journal Article] SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters (2017)
  • Author(s): Nakayama Robert T、Pulice John L、Valencia Alfredo M、McBride Matthew J、McKenzie Zachary M、Gillespie Mark A、Ku Wai Lim、Teng Mingxiang、Cui Kairong、Williams Robert T、Cassel Seth H、Qing He、Widmer Christian J、Demetri George D、Irizarry Rafael A、Zhao Keji、Ranish Jeffrey A、Kadoch Cigall
  • Journal Title: Nature Genetics Volume: 49 Issue: 11 Pages: 1613-1623
  • DOI: 10.1038/ng.3958
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 慶應義塾大学病院における骨・軟部腫瘍に対する遺伝子診断の現状と今後の展望． (2019)
  • Author(s): 中山ロバート，加藤容崇，中川瑠美，弘實透，山口さやか，浅野尚文，四十物絵理子，西原広史，中村雅也，松本守雄．
  • Organizer: 第52回 日本整形外科学会骨・軟部腫瘍学術集会
• [Presentation] 巨細胞性骨腫瘍における変異H3に対する免疫組織染色の役割． (2019)
  • Author(s): 29中山ロバート，馬場喜博，齊藤誠人，中川瑠美，弘實透，山口さやか，浅野尚文，大喜多肇，中村雅也，松本守雄
  • Organizer: 第52回 日本整形外科学会骨・軟部腫瘍学術集会
• [Presentation] SMARCB1はSWI/SNF複合体によるエンハンサー活性化に必須である (2018)
  • Author(s): 中山ロバート，Cigall Kadoch，George D. Demetri，松本守雄，中村雅也
  • Organizer: 第91回日本整形外科学会学術総会
• [Presentation] Genome-wide mistargeting of oncogenic SWI/SNF complexes in SMARCB1-deficient cancers． (2018)
  • Author(s): Nakayama R，Pulice J，Valencia A，Kadoch C，Matsumoto M，Nakamura M．
  • Organizer: 第77回日本癌学会学術集会
• [Presentation] 腫瘍抑制遺伝子SMARCB1の導入によるSWI/SNF複合体を介したエンハンサーおよびバイバレント領域のプロモーターの活性化． (2018)
  • Author(s): 中山ロバート，John L.Pulice，Cigall Kadoch，松本守雄，中村雅也．
  • Organizer: 第33回日本整形外科学会基礎学術集会
• [Presentation] SSX drives gain-of-function BAF complex chromatin affinity and genomic targeting in synovial sarcoma． (2017)
  • Author(s): McBride M，Nakayama R，Pulice J，Mashtalir N，Ingram D，Shern J，Khan J，Hornic J，Lazar A，Kadoch C
  • Organizer: American Association for Cancer Research (AACR), Washington D.C., USA
  • Int'l Joint Research
• [Presentation] SMARCB1(BAF47)欠損腫瘍における発がん性SWI/SNF(BAF)複合体のプロテオーム解析 (2017)
  • Author(s): 中山ロバート，Cigall Kadoch，George D. Demetri，森岡秀夫，中村雅也，松本守雄．
  • Organizer: 第76回日本癌学会学術総会，横浜
• [Presentation] SMARCB1の欠損はSW1/SNF複合体のクロマチンへの結合を不安定化させる． (2017)
  • Author(s): 中山ロバート，Cigall Kadoch，George D.Demetri，中村雅也，松本守雄，森岡秀夫．
  • Organizer: 第50回日本整形外科学会骨・軟部腫瘍学術集会，東京
• [Presentation] SMARCB1欠損腫瘍における発がん性SW/SNF複合体の異常な遺伝子発現制御． (2017)
  • Author(s): 中山ロバート，Cigall Kadoch，George D.Demetri，中村雅也，松本守雄，森岡秀夫
  • Organizer: 第90回日本整形外科学会学術総会，仙台