期刊
CANCER DISCOVERY
卷 6, 期 10, 页码 1148-1165出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-1481
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资金
- SPORE in Soft Tissue Sarcoma [P50 CA140146]
- MSK Cancer Center Support Grant/Core Grant [P30 CA008748]
- Siskind Family Sarcoma Fund
- MFH Research Fund
- Versus Arthritis
- Cancer Research UK [21141] Funding Source: researchfish
- Grants-in-Aid for Scientific Research [26293026] Funding Source: KAKEN
Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-alpha 10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-alpha 10, whereas normal mesenchymal cells did not. Integrin-alpha 10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-alpha 10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease. SIGNIFICANCE: Identifying the molecular pathogenesis for myxofibrosarcoma progression has proven challenging given the highly complex genomic alterations in this tumor type. We found that integrin-alpha 10 promotes tumor cell survival through activation of TRIO-RAC-RICTOR-mTOR signaling, and that inhibitors of RAC and mTOR have antitumor effects in vivo, thus identifying a potential treatment strategy for patients with high-risk myxofibrosarcoma. (C) 2016 AACR.
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