Revealing novel subtypes of synovial sarcoma through single cell transcriptomics

Synovial sarcoma (SyS) is a common type of soft tissue sarcoma, characterized by slow growth, high rates of metastasis, and diverse clinical symptoms. This malignancy is defined by the presence of the SS18-SSX fusion protein and the corresponding SS18-SSX program that promotes the core oncogenic pathways and a wide spectrum of tumor cell phenotypes. In this study, we used single-cell RNA sequencing to explore SyS diversity, highlighting four molecular subtypes. The mesenchymal NKD2⁺ SyS is characterized by the increased BMP signaling in tumor cells and the most severe immune escape and chemoresistance profile. The poorly differentiated HOXD11⁺ SyS displays the highest expression of the core oncogenic program and the likely suppression of the immune response through CXCL and MIF signaling. The fibroblast-like DCN⁺ SyS demonstrates high levels of mesenchymal differentiation, a surprising drop in the SS18-SSX program expression, and the angiogenesis-oriented cell-cell interactions. The biphasic EPCAM⁺ SyS has the highest levels of differentiation and lowest levels of the core oncogenic program. Our data complements the traditional classification of SyS and suggests that the monophasic mesenchymal SyS might consist of two molecular subtypes.