The Expression of the Immunoproteasome Subunit PSMB9 Is Related to Distinct Molecular Subtypes of Uterine Leiomyosarcoma

SIMPLE SUMMARY: Uterine leiomyosarcoma (uLMS) is a rare, aggressive, and highly heterogeneous tumor. Knockout female mice for the catalytic subunit of the immunoproteasome PSMB9 develops spontaneous uLMS. In this study, we used molecular data from 3 non-related uLMS cohorts that were integrated and analyzed by proteotranscriptomics. We observed overexpression of the immunoproteasome pathway in uLMS, and then further classified the samples as low or high PSMB9 gene expression levels and we provide evidence that; (i) in the group high there is an enrichment of pathways related to the immune system and in the group low, the ECM formation; (ii) samples with high CD8+/PSMB9 ratio shows better OS; and (iii) the main regulator in the high group is IFNγ and in the low, the proto-oncogene SRC. These findings contribute to the understanding of potential therapeutic or prognostic markers in uLMS. ABSTRACT: Background: Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the myometrium cells and whose diagnosis is based on histopathological features. Identifying diagnostic biomarkers for uLMS is a challenge due to molecular heterogeneity and the scarcity of samples. In vivo and in vitro models for uLMS are urgently needed. Knockout female mice for the catalytic subunit of the immunoproteasome PSMB9 (MIM:177045) develop spontaneous uLMS. This study aimed to analyze the role of PSMB9 in uLMS tumorigenesis and patient outcome. Methods: Molecular data from 3 non-related uLMS cohorts were integrated and analyzed by proteotranscriptomic using gene expression and protein abundance levels in 68 normal adjacent myometrium (MM), 66 uterine leiomyoma (LM), and 67 uLMS. Results: the immunoproteasome pathway is upregulated and the gene PMSB9 shows heterogeneous expression values in uLMS. Quartile group analysis showed no significant difference between groups high and low PSMB9 expression groups at 3-years overall survival (OS). Using CYBERSORTx analysis we observed 9 out of 17 samples in the high group clustering together due to high M2 macrophages and CD4 memory resting, and high CD8+/PSMB9 ratio was associated with better OS. The main pathway regulated in the high group is IFNγ and in the low is the ECM pathway dependent on the proto-oncogene SRC. Conclusion: these findings suggest 2 subtypes of uLMS (immune-related and ECM-related) with different candidate mechanisms of malignancy.