Hypoxia effects on glioblastoma progression through YAP/TAZ pathway regulation

Abstract

The resistance of glioblastomas (GBM) to standard therapies poses a clinical challenge with limited survival despite interventions. The tumor microenvironment (TME) orchestrates GBM progression, comprising stromal and immune cells and is characterized by extensive hypoxic regions. Hypoxia activates the hypoxia-inducible factor 1 alpha (HIF-1α) pathway, interacting with the Hippo pathway (YAP/TAZ) in crucial cellular processes. We discuss here the related signaling crosstalk between YAP/TAZ and regions of hypoxia in the TME with particular attention on the MST1/2 and LATS1/2-regulated YAP/TAZ activation, impacting cell proliferation, invasion, and stemness. Moreover, the hypoxia-YAP/TAZ axis influence on angiogenesis, stem cells, and metabolic regulators is defined. By reviewing extracellular matrix alterations activation of YAP/TAZ, modulation of signaling pathways we also discuss the significance of spatial constraints and epigenetic modifications contribution to GBM progression, with potential therapeutic targets in YAP/TAZ-mediated gene regulation. Comprehensive understanding of the hypoxia-Hippo pathway-TME interplay offers insights for novel therapeutic strategies, aiming to provide new directions for treatment.

Keywords: Glioblastoma; Hippo; Hypoxia; Tumor microenvironment; YAP/TAZ.