Abstract 1093: Epithelial-to-mesenchymal transition conveys resistance to restrictive growth conditions through increased autophagic flux

Abstract

Abstract Tumor progression requires cancer cells to adapt to varying microenvironments both in the primary tumor and in metastatic end organs. Metastasis is enhanced by epithelial-to-mesenchymal transition (EMT), which facilitates invasiveness and confers resistance to local stresses, such as hypoxia and nutrient limitation, although EMT is not necessarily required for these processes. Among these stressors, growth-factor (GF) deprivation may induce or select for cells that bear the hallmarks of EMT (EMT-like cells). The mechanisms by which EMT-like cells survive GF deprivation (restrictive growth conditions), which may occur when metastatic cancer cells are removed from GFs resident in the primary tumor microenvironment, remain largely uncertain. Herein we show that EMT confers upon cells the ability to maintain proliferative potential, following extended serum deprivation. We found that EMT-like prostate cancer cells (TEM 4-18) demonstrate elevated survival and reduced senescence compared to their more epithelial counterparts (PC-3E) in both short- and long-term exposure to serum withdrawal. In addition, resistance to anchorage-dependent growth-induced apoptosis (Anoikis) due to elevated autophagy is also evident in EMT-like cells. Forced expression of snail1 conferred survival advantages to PC-3 cells. Conversely, CRISPR-mediated knockout of Zeb1 reversed EMT status in TEM4-18 cells and survival advantage in restrictive growth conditions. We found that EMT-like cells exhibit elevated autophagic flux. Genetic interference with autophagy in EMT-like cells reversed their survival advantage and increased senescence in restrictive growth conditions as well as anoikis resistance. Our results suggest that the metastatic capabilities of EMT-like cells depend not only on their established invasive characteristics, but also on increased autophagy tied to the EMT-like state, and its role in surviving restrictive growth conditions. Citation Format: Lei Zhao, Jones Nauseef, Marisa Buchakjian, Matthew Barnes, Michael Henry. Epithelial-to-mesenchymal transition conveys resistance to restrictive growth conditions through increased autophagic flux [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1093.