DGAT1 as a Racially Divergent Driver of Carcinoma-Associated Fibroblast Activation Drives Tumorigenic Pathways via...

The incidence of lethal prostate cancer (PCa) is disproportionately higher in African American (AA) men compared to Caucasian (Cau) men. Racial differences in lipid reprogramming have been implicated in PCa progression. Recent studies identified race-specific biological alterations in carcinoma-associated fibroblasts (CAF). Here, we demonstrate that lipid-laden CAF from AA patients (AA ^CAF ) exhibits enhanced pro-tumorigenic functions compared to CAF from Cau patients (Cau ^CAF ).

DGAT1-regulated genes in fibroblasts were identified by transcriptomic profiling, and their biological consequences were evaluated in vivo. Patient-derived CAF from AA and Cau men were examined to determine their molecular response to DGAT1 inhibition during tumorigenesis.

Lipid droplet (LD) biogenesis analysis revealed DGAT1-dependent LD accumulation in AA ^CAF . DGAT1 overexpression in fibroblasts enhanced fibroblast activation protein (FAP1) expression and promoted in vivo tumorigenicity of cancer cells. Transcriptome and secretome profiling identified novel DGAT1-regulated genes associated with metabolism, cell-cell signaling, motility, and angiogenesis, largely mediated through the ERK1/2 pathway. Importantly, DGAT1 inhibition in patient-derived CAF elicited racially divergent regulation of pro-tumorigenic mediators, including BDNF, VEGF, and TSP1.

Our findings reveal elevated DGAT1 expression in AA ^CAF as a targetable enzymatic driver that enhances fibroblast activation and supports adaptation to a lipid-rich tumor microenvironment, thereby promoting tumorigenesis.