Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2020-10-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.141514 |
| _version_ | 1819111258499055616 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Zhiguo Chen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T03:54:45Z |
| format | Article |
| id | doaj.art-c7767e2f0eef47f9a10e9ecb1c27e92d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-22T03:54:45Z |
| publishDate | 2020-10-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-c7767e2f0eef47f9a10e9ecb1c27e92d2022-12-21T18:39:54ZengAmerican Society for Clinical investigationJCI Insight2379-37082020-10-01520Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signalingZhiguo ChenStephen LiJuan MoEric HawleyYong WangYongzheng HeJean-Philippe BrosseauTracey ShipmanD. Wade ClappThomas J. CarrollLu Q. LeSchwannomas 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.https://doi.org/10.1172/jci.insight.141514GeneticsOncology |
| spellingShingle | 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 Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling JCI Insight Genetics Oncology |
| title | Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling |
| title_full | Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling |
| title_fullStr | Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling |
| title_full_unstemmed | Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling |
| title_short | Schwannoma development is mediated by Hippo pathway dysregulation and modified by RAS/MAPK signaling |
| title_sort | schwannoma development is mediated by hippo pathway dysregulation and modified by ras mapk signaling |
| topic | Genetics Oncology |
| url | https://doi.org/10.1172/jci.insight.141514 |
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