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

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.

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

“…Quetiapine presented a broad range of effects with significant downregulation of the core Hippo genes and the transcriptional factors of the Hippo pathway, complemented by a variety of significant but multidirectional (up-and downregulated) effects on the interacting pathways. Although the precise effects of quetiapine remain to be elucidated, we speculate that it could involve effects besides the NF2 effects described above, as NF2 activity also upregulates numerous pro-inflammatory signaling pathways, including PI3K-AKT, MAPK, and ERK [27,50].…”

“…NF2 plays an indispensable role in the recruitment of MST1/2 and LATS1/2 to the plasma membrane, which enables LATS1/2 phosphorylation and repression of YAP/TAZ and MOB1 [23][24][25]. Complete abrogation of NF2 activity results in an inability to suppress the activity of YAP/TAZ [26,27]. WWC1, WWC2, and WWC3 are another family that positively regulates the Hippo pathway via the activation of LATS1/2 [28,29].…”

Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19

“…To compute reversal scores, we used a non-parametric rank-based method similar to the Kolmogorov–Smirnov test statistic. This analysis was originally suggested by the creators of the CMap database and has since been implemented in a variety of different settings 16 – 19 , 22 , 28 . As also described by others, the drug signature is compared with the gene expression profiles.…”

“…The underlying hypothesis is that for a given disease signature consisting of a set of up and down-regulated genes, if there is a drug profile where those same sets of genes are instead down-regulated and up-regulated, respectively, then that drug could be therapeutic for the disease. This method based on the Kolmogorov–Smirnov (KS) test statistic has shown promising results for a variety of different indications, including inflammatory bowel disease 17 , dermatomyositis 18 , cancer 19 – 21 , and preterm birth 22 .…”

The Hippo pathway: Horizons for innovative treatments of peripheral nerve diseases

“…135,[147][148][149][150] A very recent study confirmed this hypothesis by demonstrating that Hippo signaling and YAP/TAZ are required for schwannoma formation. 151 For patients with neurofibromatosis type 1 (NF-1), the incidence of malignancy is significantly greater. About 10% of patients with NF-1 will develop a MPNST during their lifetimes, and nearly 50% of patients with MPNST have NF- 135 Despite the fact that YAP in Schwann cell itself is not necessary for axonal regrowth or remyelination following injury, further removal of YAP in of NF2-Schwann cells null crushed nerves leads to normal axonal regrowth and functional recovery after injury.…”