Abstract A017: A new mouse model of SS18-SSX fusion oncogene driven Synovial Sarcomas

Abstract Synovial sarcomas (SS) are driven by the SS18-SSX fusion oncogene, generated by the pathognomonic t(X; 18) translocation. In genetically engineered Rosa26LSL-SS18-SSX2 mice, conditional activation of the fusion oncogene in defined lineages, such as the skeletal muscle, leads to tumor formation. However, tissue-specific activation through Cre-driver crosses has notable limitations for tumor modeling, including multifocal tumor induction, difficulty in identifying early lesions, and potential toxicities associated with widespread expression of the fusion oncogene. Local induction of SS in the Rosa26LSL-SS18-SSX2 mice by injecting TAT-CRE protein overcomes some of these limitations but has long and variable tumor latency. To overcome these limitations, we developed a next-generation SS mouse model in which Cre protein is locally delivered via intramuscular injection to simultaneously induce SS18-SSX expression, Pten deletion, and β-catenin activation. This strategy generates tumors at the injection site within three weeks with 100% penetrance. The resulting tumors—and cell lines derived from them—exhibit aggressive growth and faithfully recapitulate the histologic and molecular features of human SS. While SS has traditionally been considered immunologically “cold” due to its low mutation burden, our studies using this model reveal the presence of active immunosuppressive mechanisms that constrain the initiation and propagation of adaptive immune responses. Dissecting and therapeutically targeting these suppressive pathways may therefore provide new avenues for effective immunotherapy in SS. Citation Format: Hesham Mohei, Malay Haldar. A new mouse model of SS18-SSX fusion oncogene driven Synovial Sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A017.