TGFß-elicited pericyte dysfunction in aggressive prostate cancer

Pericytes are intrinsic components of vessels that regulate vascular stability and permeability. Aberrant vascularization is a hallmark of cancer, although the contribution of pericytes to this process is poorly understood. Here, we undertook a combined computational and experimental strategy to identify the molecular reprogramming of prostate pericytes during cancer pathogenesis and progression. Analysis of human prostate cancer and murine mouse models showed that prostate tumors exhibit a disequilibrium between endothelial and pericyte content with prognostic potential. Deeper molecular analysis revealed that there is no overt loss of pericytes in prostate tumors, but rather a disfunction that is concomitant with altered expression of a subset of cellular markers. We translate this finding into a simplified signature that discriminates pericyte abundance versus function. Leveraging single-cell RNA sequencing data, we find that TGFß governs the molecular changes that underlie pericyte disfunction in tumors. This mechanism is associated with reduced pericyte contractility, enlargement of vascular lumen and increased permeability in prostate cancer. Altogether, this study revisits the paradigm of reduced number of pericyte in favor of their disfunction in tumors, and the importance of paracrine signaling in this process. Overall design: To unravel the biological and functional consequences of paracrine TGFß signaling in brain pericytes, we performed bulk RNA sequencing on cultured pericytes treated with TGFß1 (5 µg/mL, PeproTech, #167100-21-B) or vehicle for 48 hours. Bulk RNA-Seq was conducted to investigate the differential gene expression in pericyte cultures treated with TGFß1. Eight primary pericyte cultures derived from brain tissue were used. Four cultures were treated with TGFß1 for 48 hours, while the other four were treated with vehicle as controls.