DGAT1 Drives Racially Divergent Fibroblast Activation via ERK1/2-Dependent Tumorigenic Signaling in Prostate Cancer.

UNLABELLED: Lethal prostate cancer disproportionately affects African American (AA) men, who experience a higher incidence and earlier onset compared with European American (EA) men, reflecting a persistent biological and clinical disparity. Recent studies have implicated race-associated differences in lipid metabolic reprogramming as key contributors to this disparity. We recently identified carcinoma-associated fibroblasts (CAF) as a major stromal component that mediates racial disparities in tumor progression. Here, we demonstrate that lipid-laden CAFs from AA patients (AACAF) display enhanced protumorigenic properties compared with CAFs from EA patients (EACAF). Lipid droplet (LD) biogenesis and storage analysis revealed a robust diacylglycerol O-acyltransferase 1 (DGAT1) enzyme-dependent LD accumulation in AACAF. Ectopic DGAT1 expression in benign fibroblasts induced CAF markers' (FAP1 and αSMA) expression linked to fibroblast activation, altered the secretome, and significantly enhanced prostate cancer cells' growth in vivo. Integrative transcriptomic and secretome analyses identified novel DGAT1-regulated genes involved in CAF linked to metabolism, cell-cell communication, motility, and angiogenesis, mediated mainly through ERK1/2 signaling activation. Pharmacologic DGAT1 inhibition suppressed these pathways and elicited racially distinct regulation of tumor-promoting mediators, including BDNF, VEGF, and TSP1. Mechanistic experiments show that functionally, lipid-laden CAFs from AA patients exhibit increased fibroblast activation and a secretory phenotype with greater protumor activity compared with CAFs from EA patients. Collectively, these findings reveal that DGAT1 is a pivotal enzymatic regulator of fibroblast activation and lipid-driven remodeling in the prostate cancer tumor microenvironment of AA men. Targeting DGAT1 represents a promising strategy to disrupt metabolic-stromal cross-talk and mitigate race-associated disparities in prostate cancer progression.

SIGNIFICANCE: This study highlights DGAT1-driven lipid accumulation in CAFs from AA patients with prostate cancer as a key driver of fibroblast activation and tumor-promoting roles contributing to racial disparities. Targeting DGAT1 disrupts lipid-mediated cancer-stroma interactions, offering a new therapeutic strategy to reduce aggressive prostate cancer in AA men.