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Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas.
Mazuelas, Helena; Magallón-Lorenz, Miriam; Uriarte-Arrazola, Itziar; Negro, Alejandro; Rosas, Inma; Blanco, Ignacio; Castellanos, Elisabeth; Lázaro, Conxi; Gel, Bernat; Carrió, Meritxell; Serra, Eduard.
Afiliación
  • Mazuelas H; Hereditary Cancer Group, Translational Cancer Research Program, and.
  • Magallón-Lorenz M; Hereditary Cancer Group, Translational Cancer Research Program, and.
  • Uriarte-Arrazola I; Hereditary Cancer Group, Translational Cancer Research Program, and.
  • Negro A; Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
  • Rosas I; Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, Spain.
  • Blanco I; Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
  • Castellanos E; Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, Spain.
  • Lázaro C; Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
  • Gel B; Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, Spain.
  • Carrió M; Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
  • Serra E; Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, Spain.
JCI Insight ; 9(3)2024 Jan 04.
Article en En | MEDLINE | ID: mdl-38175707
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 ogerin-selumetinib 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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Triazinas / Neurofibromatosis 1 / Neurofibroma Aspecto: Patient_preference Límite: Humans Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Triazinas / Neurofibromatosis 1 / Neurofibroma Aspecto: Patient_preference Límite: Humans Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos