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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/209920
Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas
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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.
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MAZUELAS, Helena, MAGALLÓN LORENZ, Miriam, URIARTE ARRAZOLA, Itziar, NEGRO, Alejandro, ROSAS, Inma, BLANCO, Ignacio, CASTELLANOS, Elisabeth, LÁZARO GARCÍA, Conxi, GEL MORENO, Bernat, CARRIÓ, Meritxell, SERRA ARENAS, Eduard. Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas. _JCI Insight_. 2024. [consulta: 10 de desembre de 2025]. ISSN: 2379-3708. [Disponible a: https://hdl.handle.net/2445/209920]