The Hippo signaling pathway in pediatric brain tumors: molecular mechanisms and therapeutic opportunities

Pediatric brain tumors are the second most prevalent malignancy in children with therapeutic options remaining challenging due to vulnerability of the developing brain and the significant side effects of current treatment with targeted therapies offering a promising alternative strategy. The Hippo signaling pathway has emerged as a promising molecular approach since it effectively integrates biochemical and mechanical cues to regulate cell growth and survival, tissue integrity and stem cell behaviour through interaction with major signalling pathways such as Wnt-β-catenin, TGF-β/SMAD, PI3K/Akt/mTOR, GPCR, Notch, Hedgehog and MAPK/ERK. Dysregulation of Hippo signaling has been associated with a broad range of human diseases, including cardiovascular disease, skeletal and neurodegenerative disorders, as well as multiple pediatric malignancies. Activation of the transcriptional co-activators YAP/TAZ-TEAD has proved essential for tumor growth and progression of high-grade pediatric tumors harbouring RTK or histone H3 mutations. Recent data show that YAP activation can distinguish glioblastomas from low-grade tumors in the context of MAPK and PI3K activation while YAP suppression inhibits cell proliferation and tumor growth in vivo. Herein, we describe the molecular mechanisms underlying Hippo pathway dysregulation in pediatric gliomas and propose potential therapeutic strategies for effective targeting in different subsets of pediatric brain tumors.