Abstract 2192: Stress-induced reprogramming of epithelial cancers toward a stem-like fate

Abstract

Abstract Cancer cell plasticity has become a focus of intense study as it impacts both therapy and drug resistance. Epigenetic changes contributing to cellular plasticity and stemness allow tumor cells to adapt to microenvironmental stress and or drug treatment. We recently reported that the heterodimer integrin receptor αvβ3 serves as a marker of stem-like breast, lung, and pancreatic carcinomas that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. In fact, αvβ3 was found to be both necessary and sufficient to drive stemness, drug resistance, and tumor progression. Here, we report that β3 expression is expressed in response to a range of cellular stresses, including nutrient deprivation, hypoxia, oxidative stress, and cancer therapy. Stress-induced β3 gene expression is enhanced by epigenetic histone modifications that promote an open chromatin state enabling binding of the HNF4A transcription factor to the β3 promoter. Once expressed, β3 induces reprogramming toward a stem-like fate by driving a subset of NFκB target genes, including FOXP1, a transcription factor that controls expression of pluripotency genes OCT4 and NANOG. Therefore, stress-induced chromatin remodeling and the HNF4A-mediated induction of β3 expression triggers a switch from an epithelial to a cancer stem-like phenotype. Evidence is provided that pharmacological blockade of this epigenetic change not only inhibits β3 expression but reverses tumor stem-like properties and enhances their response to therapeutic standard of care. These findings define a stress-induced but reversible epigenetic pathway leading to β3 expression on a range of epithelial cancers that drives cancer stemness, tumor progression and drug resistance. Citation Format: Maricel C. Gozo, David A. Cheresh, Mayra Yebra, Laetitia Sequin. Stress-induced reprogramming of epithelial cancers toward a stem-like fate. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2192. doi:10.1158/1538-7445.AM2015-2192