TY - JOUR
T1 - Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling
AU - Chen, Zhiguo
AU - Li, Stephen
AU - Mo, Juan
AU - Hawley, Eric
AU - Wang, Yong
AU - He, Yongzheng
AU - Brosseau, Jean Philippe
AU - Shipman, Tracey
AU - Clapp, D. Wade
AU - Carroll, Thomas J.
AU - Le, Lu Q.
N1 - Funding Information:
We thank all members of the Le laboratory for helpful suggestions and discussions, Renee McKay for critical review and editing of the manuscript, and Megan Cermak for generating the initial mouse crosses and phenotype observation. SL is supported through the Medical Scientist Training Program and an F30 fellowship from the National Institute of Aging of the NIH (F30AG056075). JM and JPB are Early Investigator Research Awardees from the US Department of Defense. LQL holds the Thomas L. Shields, MD Professorship in Dermatology. TJC was supported by funding from CPRIT RP160340 and the NIH R01DK095057. Mouse strains were provided by the UT Southwestern George M. O’Brien Kidney Research Core Center P30DK079328. DWC was supported by funding from US Department of Defense grant no. NF170058. This work was supported by funding from the National Cancer Institute of the NIH (grant no. R01 CA166593) and the U.S. Department of Defense (grant no. W81XWH -17-1-0148) to LQL.
Publisher Copyright:
Copyright: © 2020, Chen et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2020/10/15
Y1 - 2020/10/15
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.141514
DO - 10.1172/jci.insight.141514
M3 - Article
C2 - 32960816
AN - SCOPUS:85093538631
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 20
M1 - 141514
ER -