Synovial Sarcoma Preclinical Modeling: Integrating Transgenic Mouse Models and Patient-Derived Models for Translational Research

SIMPLE SUMMARY: Synovial sarcoma (SyS) is a rare malignant tumor mainly occurring in children, adolescents, and young adults. SyS displays the pathognomonic t(X;18) translocation resulting in the SS18-SSX fusion protein being able to interact with both the BAF enhancer complexes and polycomb repressor complexes, and either activate or repress gene transcription, resulting in genome-wide epigenetic deregulation and altered gene expression. This review analyzes the different experimental in vivo models for SyS research: (I) conditional transgenic mouse models expressing the SS18-SSX fusion protein that, alone or combined with some of the few other recurrent alterations (gains in BCL2, Wnt-β-catenin signaling, FGFR family, or loss of PTEN and SMARCB1), spontaneously develop SyS; (II) SyS patient-derived xenografts (PDX) established in immunodeficient mice; (III) SyS cell lines and cell line-derived xenografts. SyS preclinical models are greatly contributing to the disclosure of additional vulnerabilities and to the development of new therapeutic approaches for SyS. ABSTRACT: Synovial sarcomas (SyS) are rare malignant tumors predominantly affecting children, adolescents, and young adults. The genetic hallmark of SyS is the t(X;18) translocation encoding the SS18-SSX fusion gene. The fusion protein interacts with both the BAF enhancer and polycomb repressor complexes, and either activates or represses target gene transcription, resulting in genome-wide epigenetic perturbations and altered gene expression. Several experimental in in vivo models, including conditional transgenic mouse models expressing the SS18-SSX fusion protein and spontaneously developing SyS, are available. In addition, patient-derived xenografts have been estab-lished in immunodeficient mice, faithfully reproducing the complex clinical heterogeneity. This review focuses on the main molecular features of SyS and the related preclinical in vivo and in vitro models. We will analyze the different conditional SyS mouse models that, after combination with some of the few other recurrent alterations, such as gains in BCL2, Wnt-β-catenin signaling, FGFR family, or loss of PTEN and SMARCB1, have provided additional insight into the mechanisms of synovial sarcomagenesis. The recent advancements in the understanding of SyS biology and improvements in preclinical modeling pave the way to the development of new epigenetic drugs and immunotherapeutic approaches conducive to new treatment options.