Year: 2016
Type: conference-abstract
Abstract: GBM patients are uniformly treated with chemo-radiation, but the tumor invariably recurs and the exact molecular mechanisms driving treatment resistance in GBMs are unknown. Newer molecular targeted therapies including VEGF inhibitors, have failed to extend the dismal (approximately 14.6 month median) survival in GBM. Of the molecular subtypes of GBM, the mesenchymal (MES) subtype is considered most aggressive and we have recently shown that these cells exhibit radio-resistance in a NF-κB dependent manner. Prospectively identifying the MES subset of radio-resistant, cancer stem cells has been challenging due to a lack of cell surface markers to identify these populations. In this study we discovered CD109 as a novel tumor initiation marker for the MES subtype of glioma stem cells. Here we report that exposure of glioma stem-like cells (GSCs) to ionizing radiation (IR) promotes a persistent transcriptomic and phenotypic shift toward a MES subtype in a CD109-dependent manner. We observed that in both de novo and IR-induced MES GSCs, CD109+, but not CD109- populations are highly clonogenic in vitro and radio-resistant and tumorigenic in vivo. In addition, inhibition of CD109 through shRNAs attenuates clonogenicity, tumor propagation and radio-resistance and dramatically inhibits YAP/TAZ signaling in MES GSCs. In support of these results, CD109 is significantly associated with the MES subtype of GBMs, correlates with YAP/TAZ expression, and poorer prognosis of GBM patients.
Source: Neuro-Oncology
Authors: Alessandra Audia, Mutsuko Minata, Xing Guo, Farah Mukheef, Hetshree Patel, Ravesanker Ezhilarasan, Erik Sulman, Ichiro Nakano, Krishna Bhat
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2588100699