Lincoln A Edwards
Weill Cornell Medicine, USA
Title: Elucidating the mechanisms that underlie brain cancer stem cell regulation
Biography
Biography: Lincoln A Edwards
Abstract
Cancer stem cells are a small subset of cells that drive the propagation and the initiation of certain cancers. In glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, glioma stem cells (GSCs) can affect patient survival by imparting the virulence of unabated tumor growth through cancer stem cell self-renewal and the inhibition of GSC differentiation. The molecular mechanisms underpinning these properties of GSCs are poorly understood. Here we show that ZEB1 (Zinc Finger E-Box-Binding Homeobox 1) regulates stem cell self-renewal and differentiation (stemness) and its deletion negatively impacts patient survival. DNA pull down experiments confirmed novel E-box-ZEB1 binding sites within the promoter region of the stemness promoting factor LIF, allowing ZEB1 to repress LIF activation. We have identified that a majority of GBM patients (n>500) bear ZEB1 deletion with frequent loss of heterozygosity, leading to LIF and subsequent stem cell activation. Mimicking ZEB1 loss with ZEB1 knockdown in GSCs resulted in the induction of LIF commensurate with GSC self-renewal and inhibition of differentiation. Exposure of GSCs to IFN-γ, which causes ZEB1 induction, aborted these GSC characteristics. These findings run counter to the present literature, which would suggest that ZEB1 expression increases tumorigenicity. Surprisingly, our findings illustrate that the loss of the ZEB1 gene is common in glioblastomas and that ZEB1 loss is associated with propagation of the glioma stem cell population. This implies a biologically selective role for ZEB1 that when mutated or deleted favors propagation particularly of the cancer stem cell component. These findings link ZEB1 loss to stemness with actionable implications for prognostication and treatment.