Filipovich, Y. | Search bioRxiv

bioRxiv2025

DGAT1 as a Racially Divergent Driver of Carcinoma-Associated Fibroblast Activation Drives Tumorigenic Pathways via ERK1/2 Signaling in Prostate Cancer.

BackgroundThe 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 (AACAF) exhibits enhanced pro-tumorigenic functions compared to CAF from Cau patients (CauCAF). MethodsDGAT1-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. ResultsLipid droplet (LD) biogenesis analysis revealed DGAT1-dependent LD accumulation in AACAF. 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. ConclusionsOur findings reveal elevated DGAT1 expression in AACAF as a targetable enzymatic driver that enhances fibroblast activation and supports adaptation to a lipid-rich tumor microenvironment, thereby promoting tumorigenesis.

cancer biology↗

bioRxiv2024

Infiltrating lipid-rich macrophage subpopulations identified as a regulator of increasing prostate size in human benign prostatic hyperplasia

Macrophages exhibit marked phenotypic heterogeneity within and across disease states, with lipid metabolic reprogramming contributing to macrophage activation and heterogeneity. Chronic inflammation has been observed in human benign prostatic hyperplasia (BPH) tissues, however macrophage activation states and their contributions to this hyperplastic disease have not been defined. We postulated that a shift in macrophage phenotypes with increasing prostate size could involve metabolic alterations resulting in prostatic epithelial or stromal hyperplasia. Single-cell RNA-seq of CD45+ transition zone leukocytes from 10 large (>90 grams) and 10 small (<40 grams) human prostates was conducted. Macrophage subpopulations were defined using marker genes. BPH macrophages do not distinctly categorize into M1 and M2 phenotypes. Instead, macrophages with neither polarization signature preferentially accumulate in large versus small prostates. Specifically, macrophage subpopulations with altered lipid metabolism pathways, demarcated by TREM2 and MARCO expression, significantly accumulate with increased prostate volume. TREM2+ and MARCO+ macrophage abundance positively correlates with patient body mass index and urinary symptom scores. TREM2+ macrophages have significantly higher neutral lipid than TREM2- macrophages from BPH tissues. Lipid-rich macrophages were observed to localize within the stroma in BPH tissues. In vitro studies indicate that lipid-loaded macrophages increase prostate epithelial and stromal cell proliferation compared to control macrophages. These data define two new BPH immune subpopulations, TREM2+ and MARCO+ macrophages, and suggest that lipid-rich macrophages may exacerbate lower urinary tract symptoms in patients with large prostates. Further investigation is needed to evaluate the therapeutic benefit of targeting these cells in BPH.

immunology↗