Abstract A019: Neoplastic co-option of epithelial-immune interactions in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is initiated by a complex interplay between genetic and environmental insults that induce a marked remodeling of the pancreatic epithelium and its immune cell landscape. These tissue changes are highly reminiscent of wound healing responses, yet they critically contribute to disease pathogenesis. How regenerative tissue plasticity is co-opted to drive PDAC pathogenesis remains poorly understood. Our recent work identified cancer-associated chromatin alterations in the pre-malignant pancreatic epithelium that are induced by cooperative effects of mutant KRAS and tissue damage (inflammation). These synergistic processes aberrantly activate several cell communication factors, such as IL-33, that establish an expansive communication network among selective KRAS-mutant subpopulations and their immune environment that contributes to tumor development (Alonso-Curbelo et al., Nature 2021; Burdziak*, Alonso-Curbelo* et al., Science 2023). These epigenetically-activated communication networks are not shared with physiological regenerative processes, and represent a molecular groundwork to understand (onco)gene-environment cooperation and identify early, tumor-specific cancer mechanisms. They also provide new opportunities at the intersection of cancer biology, epigenetics and immuno-oncology for exploiting cell-cell communication traits of early KRAS-mutant cells and their niches to block the emergence and progression of neoplastic lineages. To address these questions, we are integrating single-cell genomics profiling, functional perturbations, and multiplexed tissue analyses to identify early molecular programs responsible for co-opting immune responses in PDAC, define how these shape influence tumor evolution, and identify crosstalk networks sustaining disease maintenance. Ultimately, a deeper mechanistic understanding of how early epigenetic dysregulation directs regenerative immune responses towards cancer will expose new therapeutic concepts to selectively target pro-tumor inflammation without impairing homeostatic tissue responses. Citation Format: Direna Alonso-Curbelo. Neoplastic co-option of epithelial-immune interactions in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A019.