Abstract A050: Single nuclei "AdipoMap" from esectable PDAC demonstrates differences in the visceral adipose tissue microenvironment related to obesity status

Abstract Introduction: Obesity is a modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC). It drives inflammation and adipose tissue dysfunction, promoting tumor progression via altered metabolic signaling and adipose-derived stromal cells (ADSCs) that may differentiate into cancer-associated fibroblasts (CAFs) through possible adipose-tumor crosstalk. Further, obesity impairs adipose beiging, thermogenic reprogramming of white adipocytes, promoting metabolic dysfunction associated with pro-tumorigenic signaling. The cellular heterogeneity of the visceral adipose tissue microenvironment (ATM) in obesity-associated PDAC remains unclear, limiting our understanding of the drivers related to disease progression that can be leveraged for cancer prevention. Methods: Single nuclei RNA-seq was performed on the visceral adipose tissue (VAT) from 20 patients with resectable PDAC evenly stratified by obesity status (obese, OB, BMI ≥30 kg/m2, n=10; non-obese, non-OB, BMI 30 kg/m2, n=10). Data integration and clustering/subset analysis were performed with Harmony and Seurat, respectively, followed by differential gene expression analyses (DGEA) and ingenuity pathway enrichment analysis (IPA). Results: Overall, the VAT cellular composition was similar between groups except for elevated myeloid and reduced mesothelial cells in the OB group. In both groups, 9 adipocyte cell clusters were identified, 5 white (wAd1-5), 1 white-beige transitional (wbAd1), and 3 beige (bAd1-3). In the OB group, wAd4, wAd5 and bAd1 were less abundant than in the non-OB group. DGEA of all adipocytes in the OB group showed upregulation of FOS/JUN/AP-1 signaling compared to the non-OB group, with bAd1 and bAd2 showing increased TGF-β stress signaling in the OB group. Moreover, IPA showed reduced lipid metabolism and increased inflammatory, immune, and oxidative stress signaling in wAd1-5, and reduced thermogenesis and increased growth signaling and cytoskeletal remodeling pathways in bAd1-3 in the OB group. In both groups, 8 ADSC clusters were identified, an ICAM1+ ADSC, a DPP4+ ADSC, and 6 additional ADSCs (ADSC1-6). In the OB group, ICAM1+ ADSC, DPP4+ ADSC, ADSC2, and ADSC5 were less abundant, while ADSC6 was more abundant. In both groups, all ADSCs, except ICAM1+ ADSCs, expressed a gene signature (APOD, CFD, CXCL12, MGP, Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A050.