Investigating YAP-dependent angiogenesis in glioblastoma

Glioblastoma multiforme (GBM), the most prevalent and aggressive primary brain tumor, exhibits pronounced angiogenesis. YAP/TAZ have been found as critical candidates in vascular sprouting, vascular barrier formation, and angiogenesis. Furthermore, the dysregulation of YAP/TAZ is reported to be implicated in the development and poor prognosis of several malignancies.

In this study, the relationship between the Hippo and VEGF signaling pathways was examined in GBM. Initially, co-expression networks for GBM and healthy tissues were constructed using WGCNA, identifying potential modules enriched in Hippo and VEGF pathway genes. Differentially expressed genes (DEGs) and transcription factors were analyzed for pathway overlap and enrichment. Subsequently, the Hippo pathway transducer Yap1 was knocked out in C6 GBM cells using CRISPR/Cas9, and a rat GBM model was developed. Angiogenic effects were assessed using CAM assay, immunohistochemistry (IHC), and qPCR. Two transcription factors, including RELA and NF-κB were identified as the shared members of the Hippo and VEGF signaling pathways. In the next step, the analysis through CAM assay supported a significant decrease in the length of vessels in the treated group with conditioned medium of Yap1-KO C6 cells. Additionally, the IHC results have suggested the reduced density and neoformation of the vessels in the Yap1-KO rat GBM models. Moreover, the knockout of Yap1 resulted in a remarkable decrease in Vegf expression in the rat GBM tumors.

The results suggest a notable role for the Hippo pathway transducer Yap1 in the angiogenic procedures and highlight the potential of targeting Hippo-YAP1 signaling to enhance anti-angiogenic strategies in GBM.