Abstract B118: Investigating the tumor microenvironment’s role in lineage fate determination in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer mortality, with minimal improvements in 5-year survival over the past decade. While PDAC originates from premalignant lesions, only a minority of these lesions advance further into malignancy. Distinguishing which lesions are likely to progress would transform enabling timely preventative surgical intervention, but remains a key challenge. In addition to the more well-characterized genetic mutations associated with PDAC onset, recent studies suggest that inflammation in the pancreas microenvironment promotes epithelial chromatin accessibility remodeling to increase their plasticity. This plasticity is thought to enhance cellular sensitivity in response to local signaling cues, which varies drastically across PDAC tumors. We propose that the cell lineage fate of the premalignant epithelial cells is heavily influenced by their surrounding microenvironment. To investigate this, we are using the CosMx spatial transcriptomics platform to profile cellular composition heterogeneity across pancreatic tissue cores from KrasLSL-G12D; Trp53LSL-R172H; Pdx1-Cre (KPC) mouse model of PDAC. By analyzing spatial heterogeneity within the tumor microenvironment, we aim to delineate how local microenvironmental differences might influence epithelial lineage fate decisions into PDAC. Our findings will help understand the factors driving progression from early lesions to invasive cancer, supporting efforts in early PDAC detection and informing clinical strategies for surgical resection. Citation Format: Jennifer Claire Muscat, Eva Freckmann, Andrew S. Papanastasiou, Jennifer P. Morton, Crispin J. Miller. Investigating the tumor microenvironment’s role in lineage fate determination in pancreatic ductal adenocarcinoma 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 (18Suppl₃): Abstract nr B118.