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Abstract Understanding how pancreatic epithelial cells respond to inflammation and why some become tumorigenic and aggressive could identify new methods of early detection and novel therapeutic targets to control disease progression. Here, we leveraged an in vivo model in which mice with pancreas-specific expression of mutant Kras progress from pre-malignant intraepithelial neoplasias (PanINs) to pancreatic ductal adenocarcinoma (PDAC) following caerulein-induced chronic pancreatitis. During the transition from PanINs to PDAC, we observe two classes of neoplastic lesions: classically-described PanIN tubular structures that are highly organized and previously uncharacterized atypical highly disorganized lesions that are marked by robust integrin αvβ3 expression, observations which are consistent with human pancreatitis and PDAC. In vitro, we report that immune-, stroma-, and tumor cell-derived inflammatory cytokines induce β3 expression in a STAT3-dependent manner leading to increased integrin αvβ3. Considering that we previously established αvβ3 as a driver of cancer cell stress tolerance, drug resistance, and a stem-like phenotype, the acquisition of αvβ3 during chronic inflammation may promote tumorigenesis. Indeed, using the spontaneous tumor mouse model and xenograft models of human PDAC, we find that cells with an inability to upregulate β3 during tumor initiation fail to form tumors. These findings implicate integrin αvβ3 as a critical driver of inflammation-mediated pancreatic tumorigenesis. Citation Format: Ryan M. Shepard, Alejandro D. Campos, Zachary M. Ortega, Hiromi I. Wettersten, Tami Von Schalscha, Sara M. Weis, David A. Cheresh. Inflammation mediated expression of integrin αvβ3 potentiates KRAS driven PDAC oncogenesis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4267.
Shepard et al. (Fri,) studied this question.