Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling

Zhiguo Chen, Stephen Li, Juan Mo, Eric Hawley, Yong Wang, Yongzheng He, Jean Philippe Brosseau, Tracey Shipman, D. Wade Clapp, Thomas J. Carroll, Lu Q. Le

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Schwannomas are tumors of the Schwann cells that cause chronic pain, numbness, and potentially life-threatening impairment of vital organs. Despite the identification of causative genes, including NF2 (Merlin), INI1/SMARCB1, and LZTR1, the exact molecular mechanism of schwannoma development is still poorly understood. Several studies have identified Merlin as a key regulator of the Hippo, MAPK, and PI3K signaling pathways; however, definitive evidence demonstrating the importance of these pathways in schwannoma pathogenesis is absent. Here, we provide direct genetic evidence that dysregulation of the Hippo pathway in the Schwann cell lineage causes development of multiple schwannomas in mice. We found that canonical Hippo signaling through the effectors YAP/TAZ is required for schwannomagenesis and that MAPK signaling modifies schwannoma formation. Furthermore, cotargeting YAP/TAZ transcriptional activity and MAPK signaling demonstrated a synergistic therapeutic effect on schwannomas. Our new model provides a tractable platform to dissect the molecular mechanisms underpinning schwannoma formation and the role of combinatorial targeted therapy in schwannoma treatment.

Original languageEnglish (US)
Article number141514
JournalJCI Insight
Volume5
Issue number20
DOIs
StatePublished - Oct 15 2020

ASJC Scopus subject areas

  • Medicine(all)

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