Abstract 2866: Defining epigenetic vulnerabilities in synovial sarcoma

Abstract

Abstract Synovial sarcoma constitutes 10% of all soft-tissue sarcomas and arises most frequently in adolescents and young adults. The defining genetic event of synovial sarcoma and main driver of the disease is the translocation of the SS18 gene on chromosome 18q11 to either the SSX1 and SSX2 genes located on chromosome Xp11. The resulting SS18-SSX fusion oncogene lacks a DNA binding domain, but is thought to exert its function via interaction with transcription factors and chromatin remodelers such as polycomb-group chromatin remodeling factors, and components of the SWI/SNF complex. The fact that the fusion oncogene is the defining event in this disease suggests that, on its own, it is able to generate an epigenetic profile that drives tumorigenesis. In this study we expressed SS18-SSX2 in C2C12 myoblasts to recreate the epigenetic events driving synovial sarcoma. C2C12 myoblasts expressing SS18-SSX1/2 did not show significant differences in cell growth however became completely refractory to differentiation to myotubes. In addition, knockdown of SS18-SSX2 in a mouse synovial sarcoma cell line (derived from a mouse model in which the human SS18-SSX2 fusion oncogene is expressed in the myogenic progenitor compartment) led to strong growth arrest and induction of induction of p16 and p21 cell cycle regulators. This results support the notion that the SS18-SSX oncogene drives tumorigenesis by blocking differentiation programs and by repressing tumor suppressor genes to maintain self-renewal of synovial sarcoma cells. To identify epigenetic vulnerabilities that are specifically generated by the SS18-SSX fusion protein we screened two cell lines using an shRNA library targeting epigenetic modulators: the synovial sarcoma cell line mentioned above and C2C12 myoblasts. Three control shRNAs targeting the SS18-SSX2 oncogene were within the top depletion hits in the synovial sarcoma cell line but were neutral in the C2C12 myoblasts, validating the screen performance. To uncover SS18-SSX specific hits we concentrated in genes within this list that specifically depleted in the synovial sarcoma cell line but not in myoblasts. Genes within this list and to which at least two independent shRNAs scored were subjected to extensive one-by one validation. Our results may uncover epigenetic mechanisms required to maintain self-renewal in synovial sarcoma. Citation Format: Ana Banito, Nilgun Tasdemir, Marc Ladanyi, Scott W. Lowe. Defining epigenetic vulnerabilities in synovial sarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2866. doi:10.1158/1538-7445.AM2015-2866