Cell-autonomous complement C3 activity in prostate epithelial cells suppresses malignant transformation through tonic restrain of the MYC-tumorigenesis program 3135

Abstract Description Prostate cancer (PC) remains among the leading causes of cancer-related deaths with a better understanding of the mechanisms underlying its pathogenesis urgently needed. The synthesis of complement component C3 by tumor-infiltrating immune cells in the tumor microenvironment (TME) facilitates tumor progression via immunosuppression and angiogenesis support, denoting TME C3 as a therapeutic target. However, the role of C3 expressed by tumor cells themselves during oncogenesis remain inadequately characterized. Using data from multiple clinical PC cohorts we found that, surprisingly, C3 transcript and protein levels were significantly reduced in malignantly transformed regions when compared to benign regions of human PC tissues. C3 silencing in human benign primary prostate epithelial cells (PECs) caused uncontrolled proliferation while provision of intracellular C3a to the aggressive PC cell line DU145 reduced tumor burden in a xenograft mouse model, confirming the unexpected tumor-suppressing role of C3. Mechanistically, steady-state, endogenous C3 expression, C3a generation, and -receptor engagement in PECs maintains normal cell turnover through restraint of a PI3Kd-dependent MYC program upstream of ribosomal biogenesis. Collectively, these findings ascribe a non-traditional, tumor-suppressor function to cell intrinsic C3 and advocate for dissecting the context-specific roles of complement in malignancies to better inform on complement-targeted cancer therapies. Funding Sources NIH: ZIA/hl006223, ZIA/DK075149, R35GM138283 Swiss National Science Foundation: PCEFP3_194618 Topic Categories Immune Mechanisms of Human Disease (HUM)