Abstract 1695: Paricalcitol plus hydroxychloroquine enhances gemcitabine activity and induces mesenchymal to epithelial transition in pancreatic ductal adenocarcinoma

Abstract Epithelial mesenchymal transition (EMT) describes a process by which the epithelial cells acquire mesenchymal properties associated with increased migration, invasion, and resistance to therapy. Targeting the intercellular communications and molecular changes that enable EMT is a rational therapeutic approach in PDAC. Our group has previously reported on KPC-Luc PDAC orthotopic mouse models treated with 1. Sham, 2. paricalcitol plus hydroxychloroquine (PH), 3. gemcitabine (G), and 4. GPH. Single cell RNA sequence (scRNASeq) was performed and analyzed using hdWGCNA (high dimensional Weighted Gene Co-expression Network Analysis) and GSEA (Gene Set Enrichment Analysis) to plot and determine intracellular interactions as well as gene expression changes in various treatment conditions. GPH treatment reduces EMT, which is associated with the downregulation of the essential gene fibronectin (Fn1). Collagen and Fn1 pathways co-expression decreases in GPH-treated KPC-Luc tumors. Cancer-associated fibroblasts (CAFs) appear dominant in Collagen signaling, whereas macrophages mediate Fn1 signaling. GPH treatment reduces the expression interaction strength between ligands and receptors (Collagen-Integrin and Fn1-Cd44 or Fn1-Sdc4) compared to sham, PH, and G. This comprehensive study of cell-cell communication and molecular changes during therapy offers a deep understanding of the molecular underpinnings of PDAC-EMT and metastasis and identifies possible targets for GPH. Citation Format: Ganji Purnachandra Nagaraju, Madhu Sudhana Saddala, Sujith Sarvesh, Dhanasekhar Reddy Bandi, Ateeq Muhammed Khaliq, Ashiq Masood, Mehmet Akce, Bassel F. El-Rayes. Paricalcitol plus hydroxychloroquine enhances gemcitabine activity and induces mesenchymal to epithelial transition in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1695.