Abstract C040: Investigating oncogene-inflammation cooperativity in pancreatic cancer

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is generally diagnosed at advanced late stages when current treatments are usually ineffective. It is initiated from a poorly understood interplay between genetic mutations (mutant KRAS) and inflammatory insults that cooperatively remodel the pancreatic epithelium and its tissue environment. Through integrating innovative autochthonous mouse models, single-cell technologies, and genomics methods, we recently identified early, tumor-specific chromatin changes induced by cooperative effects between mutant KRAS and inflammation, and which establish functionally-relevant cell-cell communication networks that direct pancreatic tumorigenesis (Alonso-Curbelo et al. Nature 2021; Burdziak*, Alonso-Curbelo* et al. Science 2023). These findings provide a molecular and cellular framework to understand inflammation-driven tumorigenesis, and raise the possibility of harnessing epigenetically-dysregulated cell-cell communication traits of KRAS-mutant cells to detect or block PDAC development. Towards this end, we are currently combining single-cell multiomics, multiplexed tissue analyses, and functional approaches in pre-clinical models to identify how tissue signals shape the state and fate of early KRAS-mutant cells, define paracrine effects of these changes in reprogramming the immune microenvironment, and establish the functional significance of these interactions in disease progression. With the advent of inhibitors targeting mutant KRAS, we expect that the proposed dissection of the cell-cell crosstalk networks cooperating with mutant KRAS in driving tumor development will uncover tissue-level mechanisms that may be harnessed for the interception and rationale treatment of PDAC. Citation Format: Katharina Woess, Sandra Blázquez Araguás, Andrea Diéguez, Lidia Mateo, Direna Alonso Curbelo. Investigating oncogene-inflammation cooperativity 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 C040.

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