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

• Published in: Oncotarget 2017-09, Vol.8 (43), p.73640-73653
• Main Authors: Stanzani, Elisabetta, Martínez-Soler, Fina, Mateos, Teresa Martín, Vidal, Noemi, Villanueva, Alberto, Pujana, Miquel Angel, Serra-Musach, Jordi, de la Iglesia, Núria, Giménez-Bonafé, Pepita, Tortosa, Avelina
• Format: Article
• Language: English
• Subjects: Brain tumors; Cèl·lules mare; Drug resistance; Glioma; Gliomas; Radioteràpia; Radiotherapy; Research Paper; Resistència als medicaments; Stem cells; Tumors cerebrals
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.18363

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 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.