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, & PTGDS) linked to the ADSC precursor stage in the ADSC-to-CAF transition. Additionally, a subset of ADSC1-3 and DPP4+ ADSC nuclei expressed potential ADSC-to-CAF drivers (SFRP4 & RARRES1), with ADSC1-2 from the OB group having higher expression. Conclusion: This PDAC “AdipoMap” identifies obesity-associated differences in the ATM related to inflammation, beiging, and an ADSC-to-CAF transition, likely resulting from adipose-tumor crosstalk, that could be leveraged to prevent obesity-associated PDAC development and progression. Future work will integrate our “AdipoMap” with established PDAC atlases, use in silico modeling to infer adipose-tumor crosstalk, and validate key candidate molecular mechanisms in vitro. Citation Format: Zachary A. Hurst, Kaylin M. Chasser, Jordan M. Cloyd, Mary E. Dillhoff, Aslam Ejaz, Maria Festing, Maurice Furet, Kristyn Gumpper-Fedus, Andrew Gunderson, Phil A. Hart, Lauren F. Kanzaki, Somashekar G. Krishna, Alexus Liette, Maria M. Mihaylova, Timothy M. Pawlick, Maciej Pietzrak, Kenneth L. Pitter, Mitchell L. Ramsey, Patrick Stevens, Adaliz Tores-Rosado, Susan Tsai, Ericka Velez-Bonet, Grace Vulic, Zobeida Cruz-Monserrate. Single nuclei "AdipoMap" from esectable PDAC demonstrates differences in the visceral adipose tissue microenvironment related to obesity status [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A050.