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.

中文翻译：

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缺氧通过 YAP/TAZ 通路调节对胶质母细胞瘤进展的影响

胶质母细胞瘤（GBM）对标准疗法的耐药性带来了临床挑战，尽管采取干预措施，生存仍有限。肿瘤微环境（TME）协调 GBM 进展，包括基质细胞和免疫细胞，其特点是广泛的缺氧区域。缺氧会激活缺氧诱导因子 1 α (HIF-1α) 通路，在关键的细胞过程中与 Hippo 通路 (YAP/TAZ) 相互作用。我们在此讨论 YAP/TAZ 与 TME 缺氧区域之间的相关信号传导串扰，特别关注 MST1/2 和 LATS1/2 调节的 YAP/TAZ 激活，影响细胞增殖、侵袭和干性。此外，还确定了缺氧-YAP/TAZ 轴对血管生成、干细胞和代谢调节因子的影响。通过回顾 YAP/TAZ 的细胞外基质改变激活、信号通路的调节，我们还讨论了空间限制和表观遗传修饰对 GBM 进展的重要性，以及 YAP/TAZ 介导的基因调控的潜在治疗靶点。对缺氧-Hippo通路-TME相互作用的全面理解为新的治疗策略提供了见解，旨在为治疗提供新的方向。