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dc.contributor.authorAmmoun, Sylwia
dc.contributor.authorSchmid, MC
dc.contributor.authorRistic, N
dc.contributor.authorZhou, L
dc.contributor.authorHilton, D
dc.contributor.authorErcolano, E
dc.contributor.authorCarroll, Camille
dc.contributor.authorHanemann, Clemens Oliver
dc.date.accessioned2015-07-29T09:23:27Z
dc.date.available2015-07-29T09:23:27Z
dc.date.issued2012-11
dc.identifier.issn0894-1491
dc.identifier.issn1098-1136
dc.identifier.urihttp://hdl.handle.net/10026.1/3483
dc.description.abstract

Loss of the tumor suppressor merlin causes development of the tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas occurring spontaneously or as part of a hereditary disease Neurofibromatosis Type 2 (NF2). Current therapies, (radio) surgery, are not always effective. Therefore, there is a need for drug treatments for these tumors. Schwannomas are the most frequent of merlin-deficient tumors and are hallmark for NF2. Using our in vitro human schwannoma model, we demonstrated that merlin-deficiency leads to increased proliferation, cell-matrix adhesion, and survival. Increased proliferation due to strong activation of extracellular-signal-regulated kinase 1/2 (ERK1/2) is caused by overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) and ErbB2/3 which we successfully blocked with AZD6244, sorafenib, or lapatinib. Schwannoma basal proliferation is, however, only partly dependent on PDGFR-β and is completely independent of ErbB2/3. Moreover, the mechanisms underlying pathological cell-matrix adhesion and survival of schwannoma cells are still not fully understood. Here, we demonstrate that insulin-like growth factor-I receptor (IGF-IR) is strongly overexpressed and activated in human primary schwannoma cells. IGF-I and -II are overexpressed and released from schwannoma cells. We show that ERK1/2 is relevant for IGF-I-mediated increase in proliferation and cell-matrix adhesion, c-Jun N-terminal kinases for increased proliferation and AKT for survival. We demonstrate new mechanisms involved in increased basal proliferation, cell-matrix adhesion, and survival of schwannoma cells. We identified therapeutic targets IGF-IR and downstream PI3K for treatment of schwannoma and other merlin-deficient tumors and show usefulness of small molecule inhibitors in our model. PI3K is relevant for both IGF-IR and previously described PDGFR-β signaling in schwannoma.

dc.format.extent1721-1733
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoeng
dc.publisherWiley
dc.subjecthuman schwannoma
dc.subjectinsulin-like growth factors
dc.subjectproliferation
dc.subjectadhesion
dc.subjectsurvival
dc.titleThe role of insulin-like growth factors signaling in merlin-deficient human schwannomas
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, Non-U.S. Gov't
plymouth.author-urlhttps://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000308444000008&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008
plymouth.issue11
plymouth.volume60
plymouth.publication-statusPublished
plymouth.journalGlia
dc.identifier.doi10.1002/glia.22391
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA03 Allied Health Professions, Dentistry, Nursing and Pharmacy
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/FoH - Applied Parkinson's Research
plymouth.organisational-group/Plymouth/Research Groups/FoH - Community and Primary Care
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CCT&PS
plymouth.organisational-group/Plymouth/Research Groups/Plymouth Institute of Health and Care Research (PIHR)
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
plymouth.organisational-group/Plymouth/Users by role/Researchers in ResearchFish submission
dc.publisher.placeUnited States
dcterms.dateAccepted2012-06-22
dc.identifier.eissn1098-1136
dc.rights.embargoperiodNot known
rioxxterms.funderMedical Research Council
rioxxterms.identifier.projectMolecular genetic studies of iron metabolism in Parkinson's disease and related neurodegenerative disorders
rioxxterms.versionofrecord10.1002/glia.22391
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2012-11
rioxxterms.typeJournal Article/Review
plymouth.funderMolecular genetic studies of iron metabolism in Parkinson's disease and related neurodegenerative disorders::Medical Research Council


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