Radioresistance of mesenchymal glioblastoma initiating cells correlates with patient outcome and is associated with activation of inflammatory program

// Elisabetta Stanzani 1 , Fina Martínez-Soler 1,2 , Teresa Martín Mateos 1 , Noemi Vidal 3 , Alberto Villanueva 4,5 , Miquel Angel Pujana 4 , Jordi Serra-Musach 4 , Núria de la Iglesia 6 , Pepita Giménez-Bonafé 1 and Avelina Tortosa 1,2 1 Department of Physiological Sciences, Faculty of Medicine and Health Sciences, Universitat de Barcelona, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain 2 Department of Basic Nursing, Faculty of Medicine and Health Sciences, Universitat de Barcelona, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain 3 Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain 4 Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology, IDIBELL L’Hospitalet del Llobregat, Barcelona, Spain 5 Xenopat S.L., Bellvitge Health Science Campus, L’Hospitalet del Llobregat, Barcelona, Spain 6 Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain Correspondence to: Avelina Tortosa, email: // Fina Martínez-Soler, email: // Keywords : glioblastoma, cancer stem cells, radiotherapy, radioresistance, inflammation Received : March 16, 2017 Accepted : May 23, 2017 Published : June 03, 2017 Abstract Glioblastoma (GBM) still remains an incurable disease being radiotherapy (RT) the mainstay treatment. Glioblastoma intra-tumoral heterogeneity and Glioblastoma-Initiating Cells (GICs) challenge the design of effective therapies. We investigated GICs and non-GICs response to RT in a paired in-vitro model and addressed molecular programs activated in GICs after RT. Established GICs heterogeneously expressed several GICs markers and displayed a mesenchymal signature. Upon fractionated RT, GICs reported higher radioresistance compared to non-GICs and showed lower α- and β-values, according to the Linear Quadratic Model interpretation of the survival curves. Moreover, a significant correlation was observed between GICs radiosensitivity and patient disease-free survival. Transcriptome analysis of GICs after acquisition of a radioresistant phenotype reported significant activation of Proneural-to-Mesenchymal transition (PMT) and pro-inflammatory pathways, being STAT3 and IL6 the major players. Our findings support a leading role of mesenchymal GICs in defining patient response to RT and provide the grounds for targeted therapies based on the blockade of inflammatory pathways to overcome GBM radioresistance.