Abstract 210: Id4 inhibition of twist1-mediated autocrine PDGF signaling inhibits growth and promotes apoptosis of glioblastoma-derived stem cell cultures

Abstract

Abstract Glioblastoma Multiforme (GBM) is the most common, aggressive, and lethal primary brain tumor. A hallmark of GBM is the resistance of tumor stem cells to chemotherapy resulting in tumor recurrence and progression decreasing the quality of life and causing patient death. The prevention of GBM recurrence after chemotherapy by eliminating cancer stem cells enhances survival in genetically engineered mouse models; however, the signal transduction networks that control cancer stem cell survival and proliferation remain poorly understood. We have discovered that decreased expression of Id4, a dominant negative helix-loop-helix transcription factor, is associated with the proliferation and survival of sphere cultures from GBM-derived cell lines, which are enriched for cancer stem cells. In striking contrast, Id4 expression did not affect proliferation or apoptosis in differentiated, adherent cultures of these same cell lines. Moreover, the cell lines we examined required autocrine PDGF signaling for growth. We found that Id4 inhibited autocrine PDGF signaling in cancer stem cell enriched cultures by suppressing the expression of platelet-derived growth factor receptor α (PDGFRα). In these studies we found that Id4 mediated inhibition of PDGFRα expression was mediated through the antagonistic interaction between Id4 and Twist1, a basic helix-loop-helix transcription factor. This observation is consistent with our previously reported finding that Id4, uniquely among the Id family of proteins, binds to and antagonizes Twist1. Further, using the Rembrandt and TCGA databases, we found that Id4 expression levels directly correlate with glioma patient survival and can predict the level of PDGFRα expression. These data provide strong evidence that Id4 may regulate GBM stem cell survival and thereby contribute to GBM tumor progression. Along with our recent report demonstrating that Id4 can block invasion of GBM by silencing Twist1-mediated MMP2 expression, these findings suggest that pharmacological targeting of the Id4/Twist1 complex might provide opportunities to reduce the lethality of GBM by regulating both GBM invasion and tumor stem cell maintenance. Citation Format: Gilbert J. Rahme, Mark A. Israel. Id4 inhibition of twist1-mediated autocrine PDGF signaling inhibits growth and promotes apoptosis of glioblastoma-derived stem cell cultures. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 210. doi:10.1158/1538-7445.AM2014-210