A Role for the Hippo/YAP1 Pathway in the Regulation of In Vitro Vasculogenic Mimicry in Glioblastoma Cells

J Cell Mol Med. 2024 Dec;28(24):e70304. doi: 10.1111/jcmm.70304.

Abstract

The Hippo pathway plays a tumorigenic role in highly angiogenic glioblastoma (GBM), whereas little is known about clinically relevant Hippo pathway inhibitors' ability to target adaptive mechanisms involved in GBM chemoresistance. Their molecular impact was investigated here in vitro against an alternative process to tumour angiogenesis termed vasculogenic mimicry (VM) in GBM-derived cell models. In silico analysis of the downstream Hippo signalling members YAP1, TAZ and TEAD1 transcript levels in low-grade glioblastoma (LGG) and GBM tumour tissues was performed using GEPIA. TAZ transcript levels did not differ between the healthy and tumour tissues data analysed. In contrast, YAP1 transcript levels were elevated in GBM tissues, whereas TEAD1 levels were high in both LGG and GBM. All three Hippo pathway inhibitors tested, GNE7883, VT107 and IAG933 effectively inhibited U87 and U251 cell migration and in vitro VM as assessed on Cultrex matrix. YAP1 gene and protein expression were induced upon VM, and its translocation to the nucleus was inhibited by the Hippo pathway inhibitors tested. SiRNA-mediated transient silencing of YAP1 repressed cell migration, VM formation and CTGF and Cyr61 transcription. In conclusion, targeting of VM using Hippo pathway inhibitors could help circumvent GBM chemoresistance and effectively complement other brain cancer treatments.

Keywords: YAP/TEAD; chemoresistance; glioblastoma; hippo pathway; vasculogenic mimicry.

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement*
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Cysteine-Rich Protein 61 / genetics
  • Cysteine-Rich Protein 61 / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Glioblastoma* / blood supply
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Hippo Signaling Pathway*
  • Humans
  • Neovascularization, Pathologic* / genetics
  • Neovascularization, Pathologic* / metabolism
  • Neovascularization, Pathologic* / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Signal Transduction*
  • TEA Domain Transcription Factors* / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / metabolism
  • YAP-Signaling Proteins* / metabolism

Substances

  • Transcription Factors
  • YAP1 protein, human
  • YAP-Signaling Proteins
  • Protein Serine-Threonine Kinases
  • Adaptor Proteins, Signal Transducing
  • TEA Domain Transcription Factors
  • TEAD1 protein, human
  • Cysteine-Rich Protein 61
  • Phosphoproteins
  • DNA-Binding Proteins
  • Connective Tissue Growth Factor
  • CCN1 protein, human
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • Nuclear Proteins
  • CCN2 protein, human
  • WWTR1 protein, human