Single-Cell RNA Sequencing Reveals the Cellular and Molecular Differences Between Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma

<b>Objective:</b> Myxofibrosarcoma (MXF) and undifferentiated pleomorphic sarcoma (UPS) are common and aggressive subtypes of cancer differing by clinical characteristics and prognosis; however, their differential diagnosis is difficult. Elucidation of cellular and transcriptomic discrepancies between these diseases that could improve their identification was the aim of our study. <b>Methods:</b> We applied single-cell RNA sequencing to compare MXF and UPS by tumor cell clusters and cell-cell ligand-receptor interactions, using five tumor samples of both subtypes. <b>Results:</b> We identify nine major cell types in all tumors analyzed. Any significant differences in their proportions between MXF and UPS were not found. Further reclusterization of lymphoid cells showed that cytotoxic CD8+ T cell proportion was higher in the MXF samples. In UPS cancer cells, the pathways maintaining extracellular matrix components (including collagens, proteoglycans, and other proteins) were highly active, while MXF cells were characterized by high activity of growth factors and angiogenesis pathways. The ligand-receptor interactions between cancer cells and the microenvironment differed significantly between MXF and UPS. In UPS, CD80 of dendritic cells and macrophages prominently interacted with T cell co-inhibitory CTLA-4 receptors, whereas the activating CD80-CD28 interaction was predominant in MXF. Moreover, in UPS, CD44 and integrins of cytotoxic CD8+ T cells prominently interacted with COL1A1/2, while in MXF CD44, interaction with FN1, COL6A1, and LAMC1 prevailed. <b>Conclusions:</b> Differences were identified between UPS and MFS in the composition of lymphoid cell populations and in the intercellular interactions. This proposes deeper understanding of the biological differences between these sarcoma subtypes and may be important for the development of new therapeutic approaches, although further validation of the findings is required.