Lethal prostate cancer (PCa) disproportionately affects African American (AA) men, who experience a higher incidence and earlier onset compared to 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 (CAFs) as a major stromal component that mediates racial disparities in tumor progression. Here, we demonstrate that lipid-laden CAF from AA patients (AACAF) display enhanced pro-tumorigenic 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 ⍺SMA) expression linked to fibroblast activation, altered the secretome, and significantly enhanced PCa 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. Pharmacological 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 CAF from AA patients exhibit increased fibroblast activation and a secretory phenotype with greater pro-tumor activity compared to CAF from EA patients. Collectively, these findings reveal that DGAT1 is a pivotal enzymatic regulator of fibroblast activation and lipid-driven remodeling in the PCa tumor microenvironment (TME) of AA men. Targeting DGAT1 represents a promising strategy to disrupt metabolic-stromal crosstalk and mitigate race-associated disparities in PCa progression.
Cancer research communications. 2026 May 12 [Epub ahead of print]
Sathyavathi ChallaSivaKanaka, Mamatha Kakarla, Renee E Vickman, Yana Filipovich, Philip Fitchev, Md Maksudul Alam, Md Niaz Morshed, Pooja Talaty, Brian T Helfand, David Price, Simon W Hayward, Susan E Crawford, Omar E Franco
NorthShore University HealthSystem New York United States., NorthShore University HealthSystem Evanston, IL United States., NorthShore University HealthSystem Evanston, Illinois United States., Louisiana State University Health Sciences Center Shreveport Shreveport, LA United States., NorthShore University HealthSystem Glenview, IL United States., Louisiana State University Shreveport, LA United States.