SC-35 * BMP SIGNALING REGULATES A QUIESCENT CANCER STEM CELL PHENOTYPE RESPONSIBLE FOR TREATMENT RESISTANCE IN GLIOBLASTOMA

Abstract

Stem cell niches must be dynamic to enable stem cells to respond promptly and appropriately to physiologic demands. There is growing evidence to suggest that the superfamily of transforming growth factor-βs (TGF-βs) play an integral role in the maintenance of stem cell homeostasis within multiple stem cell systems. In glioblastoma, TGF-β has been shown to act as an oncogenic factor through its induction of self-renewal and proliferation in glioma stem cells (GSCs), and inhibition of GSC differentiation. Conversely, treatment of GSCs with BMP4 in vitro was found to direct these cells toward a differentiated, astrocytic phenotype, and abolish their ability to drive tumor growth following xenotransplantation. These studies suggest that TGF-β and BMP signaling direct glioma cells toward an irreversible fate choice, and that maintenance of the cancer stem cell (CSC) phenotype is necessary for tumorigenicity. We postulated that the CSC fate choices in glioblastoma are plastic, and that TGF-β and BMP signaling regulate cell glioma cell dynamics within the tumor microenvironment, as in cellular reprogramming. Further, we postulated that TGF-β and BMP might construe cell identities in glioblastoma that could be relevant to glioblastoma treatment resistance, disease evolution and disease progression. Here, we demonstrate that TGF-β and BMP signaling are active in the glioblastoma microenvironment, and regulate the shuttling of GSCs from an activated to a quiescent phenotype. At the molecular level, this process is mediated, as in EMT/MET, by the ZEB1/miR-200 double-negative feedback loop. Activation of p21 via BMP signaling is one mechanism for resistance to chemotherapy- and radiation-induced cell damage. Quiescent, BMPhi cells then give rise to TGF-βhi GSCs that drive tumour progression. Our findings demonstrate a role for BMP-mediated quiescence in glioblastoma disease resistance and recurrence, and suggest that targeted inhibition of BMP during chemoradiation could favorably alter the natural history of this disease.