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Abstract STAT3 represents an oncogene whose transcriptional regulation is known to drive tumor initiation, progression, and drug resistance. Although STAT3 can regulate many genes, it remains unclear which genes are critical for STAT3-mediated cancer progression. Here, we report that inflammatory cytokines and cellular stress induce STAT3 activation leading to tumor initiation and progression, which we show depends on its ability to drive transcription of the β3 integrin gene leading to αvβ3 expression. Specifically, CRISPR KO of either STAT3 or integrin β3 in pancreatic cancer cells, is sufficient to impede their tumor initiating capacity in mice, while ectopic STAT3 or β3 expression in STAT3 KO cells rescues their tumor initiation capacity. Mechanistically, STAT3 activation induces β3 expression based on its ability to engage enhancer regions that modulate β3 gene expression. These findings implicate integrin αvβ3 as a critical downstream effector of STAT3, thereby contributing to its role as a driver of tumor initiation and progression. Citation Format: Alejandro D. Campos, Ryan Shepard, Ingrid Heumann, Justin Lam, Sara M. Weis, David Cheresh. STAT3 integration of inflammatory signals and cellular stress promote tumor initiation and progression through the expression of integrin β3 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 6966.
Campos et al. (Fri,) studied this question.