TMOD-22. WILD-TYPE p53 DRIVES A MESENCHYMAL PHENOTYPE AFTER TREATMENT OF PRIMARY GLIOBLASTOMA

Glioblastoma (GBM) is the most common and aggressive adult brain malignancy for which conventional surgery, radiation treatment and chemotherapy based on alkylating agent Temozolomide (TMZ) have limited benefit. Overall survival is variable but less than 10% of GBM patients survive 5 years, making it one of the most aggressive and clinically intractable cancers. The main cause of poor prognosis is the rapid emergence of recurrent disease, despite extensive removal of cancer cells from the primary site. Here, by using patient-derived xenografts we demonstrate that GBM is fueled by a mixture of fast- and slow-cycling cells. In vivo , treatment based on TMZ triggers a transient cell arrest in G2/M and DNA damage but does not promote cell death. In particular, by causing DNA double strand breaks, TMZ induces the autophosphorylation of ataxia telangiectasia mutated (ATM S1981) and the downstream phosphorylation of histone H2AX (YH2AX). In response to TMZ, GBM cells undergo a transient switch to a p53-driven mesenchymal phenotype with significant up-regulation of CD44, Vimentin and Gfap expression. The transient phenotype switch is followed by down-regulation of p53 and the emergence of treatment-resistant GBM. Illumina-based gene expression profiling and marker analysis reveal striking similarities between matched control and treatment-resistant tumors. ChIP-seq experiments are currently ongoing to identify critical nodes of phenotype switch. We are also using genetically-engineered mouse models of gliomas to understand if wild-type p53 drives a mesenchymal phenotype in Nestin -, Gfap -, Glast -, ApoE - and Pla2 -derived tumors. Altogether, these results contribute to increase our knowledge of the biology of GBM growth and treatment resistance and identify p53 as a driver of phenotypic plasticity.