Endocrine Abstracts

JOINT1932

Glioblastoma (GBM) stands as the most prevalent and lethal primary brain endocrine cancer (ECR) due to the late-stage diagnosis and the resistance to gold standard therapy, which results in a low survival rate after diagnosis (8-9 months) and poor prognosis of patients. Consequently, the identification of novel diagnosis/prognosis biomarkers and therapeutic targets becomes critical to improve the clinical management of this devastating endocrine-related cancer. Here, we focus on the study of the inflammasome, a molecular machinery activated by cellular stress and damage which triggers the maturation and release of proinflammatory cytokines, being closely associated to the modulation of immune responses and cell death, as well as with tumor microenvironment (TME), a well-known hallmark of cancer. Specifically, we initially characterized the expression levels of the inflammasome components in a well-characterized cohort of GBM patients (n = 63) and compared with non-tumor brain (NTB; n=19) samples by using a validated qPCR array based on microfluidic technology. Our results revealed a profound dysregulation of the expression pattern of the inflammasome machinery in our cohort of GBM samples, which was later validated in different external cohorts using RNA-seq and microarray data. Remarkably, the expression of key inflammasome components, especially MYD88, was associated to several clinical parameters of aggressiveness/poor-prognosis (e.g. survival rate, recurrence, EGFR amplification and MGMT methylation status). Of note, MYD88 expression was also found to be associated with diverse pathways of relevance in GBM pathophysiology (e.g. epithelial to mesenchymal transition, hypoxia, angiogenesis or NFkB-signaling). Moreover, the modulation of the expression of MYD88 (through transitory silencing by siRNA or pharmacological inhibition) significantly reduced several key tumor functional parameters in GBM cell models in vitro, including cell-proliferation, tumorspheres or colonies formation and migration rate. Taken together, this study demonstrates the critical role of inflammasome machinery in GBM pathophysiology, highlighting the importance of MYD88 alteration as a potential driver of GBM aggressiveness. Consequently, MYD88 could serve as a novel diagnostic and/or prognostic biomarker, and potential therapeutic target that might be useful to improve the quality of life of GBM patients.