Overall: PROJECT SUMMARY/ABSTRACT (Parent Award) This application responds to RFA-CA-17-049 by proposing the establishment of a center distributed across three institutions with labs all focusing on the biology of the SS18-SSX (formerly called SYT-SSX) fusion oncogene. Among the FusOnC2 consortium cancers of interest, synovial sarcoma has the highest incidence in the United States and worldwide, but has been a specifically underserved malignancy due to its predilection for the adolescent and young adult population and its relatively poor responsiveness to systemic therapy, compared to other pediatric sarcomas that also associate with fusion oncogenes. While much of the biology of SS18-SSX remains unknown and synovial sarcoma patients represent a clearly underserved, orphan-disease population, there are two principles at the extremes of the cancer biology spectrum that are well established. First, SS18-SSX has proven the capacity to recapitulate synovial sarcomagenesis faithfully in the mouse without the need of introduced or stochastically acquired secondary genetic changes, second SS18-SSX has biochemically demonstrated interactions with an important chromatin remodeling complex called SWI/SNF or BAF. This application proposes to build three research projects focused on the cell biology of transformation, genome-wide chromatin biology and SWI/SNF (BAF) complex componentry biology, each related to SS18- SSX. These discovery biology and therapeutic target identification efforts will be supported by two shared resource cores that will provide human validation of therapeutic targets and preclinical testing of therapeutic strategies. The group of investigators has developed as an organically assembled network of collaborations, built over the last decade, during which time each project has gathered substantial preliminary data using a variety of functional screens, a newly identified cell of origin, the ability to track SS18-SSX genome wide localization and protein interactions, a powerful system to produce and evaluate recombinant SWI/SNF (BAF) complexes with variable componentry, and powerful mouse genetic models of synovial sarcoma—including spontaneous development of metastatic disease. Preliminary data are sufficiently robust to recommend therapeutic strategies immediately from each research project for the cores to validate and evaluate in clinically relevant mouse models and quantitative molecular imaging.