Endocrine Abstracts

Glioblastoma (GBM) is the most prevalent and most lethal primary brain endocrine-related cancer (ERC) in adults which, in addition to the late-stage diagnosis and the lack of effective novel therapies, results in the low quality of life of patients and the poor prognosis, with a median survival from 10 to 14 months after diagnosis. Accordingly, the identification of novel molecular biomarkers of diagnosis and/or prognosis, as well as therapeutic targets becomes crucial to combat this devastating ERC. In this context, the inflammasome molecular machinery, the master regulator of cell inflammation, could be critical in the modulation of the tumor microenvironment (TME), which is essential in the initiation, progression, aggressiveness, and endocrine alterations of different ERC types. In this work, with the objective of determining the putative pathophysiological role of this molecular machinery in GBM, we characterized the components of the inflammasome in GBM samples (n=63) from a genomic, transcriptomic, and proteomic point of view, demonstrating a profound dysregulation in comparison to non-tumor brain samples (n=19). The main results were confirmed through bioinformatic analyses using several external cohorts of patients. Interestingly, the presence of mutations in the inflammasome machinery, as well as the alteration in the transcriptional expression of key Inflammasome components such as MYD88, NLRP2, and RBP4, was found to be associated with relevant clinical parameters of prognosis such as survival rate, recurrence, and MGMT methylation status. Of note, an overall upregulation of the effectors of the inflammasome was observed, suggesting a putative activation of this machinery in GBMs that could induce the establishment of a proinflammatory TME. Moreover, we demonstrated that the inhibition of the activity of the inflammasome (using the inhibitor anakinra) failed to alter the proliferation of GBM cells but was able to successfully reverse the dysregulation in the expression pattern of the inflammasome components previously observed in GBMs in response to metformin. Taken together, our results demonstrate a profound dysregulation of the Inflammasome machinery in GBM, which could serve as a source of new diagnostic/prognostic biomarkers and therapeutic targets to combat this devastating types of ERC.