Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/209920
Title: | Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas |
Author: | Mazuelas, Helena Magallón Lorenz, Miriam Uriarte Arrazola, Itziar Negro, Alejandro Rosas, Inma Blanco, Ignacio Castellanos, Elisabeth Lázaro, Conxi Gel, Bernat Carrió, Meritxell Serra, Eduard |
Keywords: | Citogenètica Càncer Cytogenetics Cancer |
Issue Date: | 4-Jan-2024 |
Publisher: | American Society for Clinical Investigation |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.168826 |
It is part of: | JCI Insight, 2024 |
URI: | http://hdl.handle.net/2445/209920 |
Related resource: | https://doi.org/10.1172/jci.insight.168826 |
ISSN: | 2379-3708 |
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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