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http://hdl.handle.net/2445/209920
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DC Field | Value | Language |
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dc.contributor.author | Mazuelas, Helena | - |
dc.contributor.author | Magallón Lorenz, Miriam | - |
dc.contributor.author | Uriarte Arrazola, Itziar | - |
dc.contributor.author | Negro, Alejandro | - |
dc.contributor.author | Rosas, Inma | - |
dc.contributor.author | Blanco, Ignacio | - |
dc.contributor.author | Castellanos, Elisabeth | - |
dc.contributor.author | Lázaro, Conxi | - |
dc.contributor.author | Gel, Bernat | - |
dc.contributor.author | Carrió, Meritxell | - |
dc.contributor.author | Serra, Eduard | - |
dc.date.accessioned | 2024-04-15T08:12:47Z | - |
dc.date.available | 2024-04-15T08:12:47Z | - |
dc.date.issued | 2024-01-04 | - |
dc.identifier.issn | 2379-3708 | - |
dc.identifier.uri | http://hdl.handle.net/2445/209920 | - |
dc.description.abstract | Cutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Individuals with neurofibromatosis type 1 (NF1) may develop thousands of cNFs, which greatly affect their quality of life. cNF growth is driven by the proliferation of NF1-/- SCs and their interaction with the NF1+/- microenvironment. We analyzed the crosstalk between human cNF-derived SCs and fibroblasts (FBs), identifying an expression signature specific to the SC-FB interaction. We validated the secretion of proteins involved in immune cell migration, suggesting a role of SC-FB crosstalk in immune cell recruitment. The signature also captured components of developmental signaling pathways, including the cAMP elevator G protein-coupled receptor 68 (GPR68). Activation of Gpr68 by ogerin in combination with the MEK inhibitor (MEKi) selumetinib reduced viability and induced differentiation and death of human cNF-derived primary SCs, a result corroborated using an induced pluripotent stem cell-derived 3D neurofibromasphere model. Similar results were obtained using other Gpr68 activators or cAMP analogs/adenylyl cyclase activators in combination with selumetinib. Interestingly, whereas primary SC cultures restarted their proliferation after treatment with selumetinib alone was stopped, the combination of ogerinselumetinib elicited a permanent halt on SC expansion that persisted after drug removal. These results indicate that unbalancing the Ras and cAMP pathways by combining MEKi and cAMP elevators could be used as a potential treatment for cNFs. | - |
dc.format.extent | 19 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | American Society for Clinical Investigation | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.168826 | - |
dc.relation.ispartof | JCI Insight, 2024 | - |
dc.relation.uri | https://doi.org/10.1172/jci.insight.168826 | - |
dc.rights | cc by (c) Mazuelas, Helena et al, 2024 | - |
dc.source | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) | - |
dc.subject.classification | Citogenètica | - |
dc.subject.classification | Càncer | - |
dc.subject.other | Cytogenetics | - |
dc.subject.other | Cancer | - |
dc.title | Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2024-04-03T08:44:19Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 38175707 | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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jci.insight.168826.v2.pdf | 3.15 MB | Adobe PDF | View/Open |
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