Abstract 1517: G0-like cells support an oral cancer stem cell pool by transitioning to a JARID1B-high state

Abstract

Abstract Oral squamous cell carcinomas (OSCCs) likely contain a subset of tumor cells whose stem cell-like molecular and functional properties help sustain tumor growth. There is growing evidence that this cancer stem cell (CSC) pool exists in dynamic equilibrium with other subpopulations with tumorigenic potential. To characterize this plasticity in OSCC, we examined the developmental potential of tumor cells in a “G0-like” cell state previously shown to have high growth capacity and innate drug resistance in other tumor types. G0-like cells in OSCC exhibited hallmark molecular traits of low reactive oxygen species (ROS), high Hes1, and low total Akt levels. However, despite lacking high levels of CD44 and other stem cell markers, they prominently displayed stem cell-like functional properties of in vitro sphere formation and in vivo tumorigenicity. To evaluate the contribution of G0-like cells to the oral CSC pool, a GFP reporter system was used to isolate CSCs based on high expression of JARID1B, an H3K4me3 demethylase associated with multiple normal and malignant stem cell phenotypes. JARID1B-high OSCC cells were distinct from the G0-like subset, highly expressed CD44 and ALDH1, and possessed both molecular and functional CSC traits. Silencing JARID1B expanded the G0-like subset but abrogated its functional CSC properties, suggesting these cells mediate such functions by returning to a JARID1B-high CSC state. The G0-like and JARID1B-high subsets were further distinguished by widely disparate levels of PI3-kinase pathway activation, which corresponded to distinct responses to cytotoxic and targeted therapies. These findings reveal a JARID1B-mediated mechanism underlying a contribution of G0-like cells to a CSC pool. Further they may provide a novel basis for OSCC therapy by simultaneously targeting the CSCs and a subset G0-like cells that appear uniquely primed to return to a CSC state. Citation Format: Nicole Facompre, Zachary Belden, Phyllis Gimotty, Anil Rustgi, Meenhard Herlyn, Hiroshi Nakagawa, Devraj Basu. G0-like cells support an oral cancer stem cell pool by transitioning to a JARID1B-high state. [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 1517. doi:10.1158/1538-7445.AM2015-1517