Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas
Mazuelas, Helena (Hereditary Cancer Group)
Magallón-Lorenz, Miriam (Hereditary Cancer Group)
Uriarte-Arrazola, Itziar (Hereditary Cancer Group)
Negro, Alejando (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Rosas, Inma (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Blanco Guillermo, Ignacio (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Castellanos, Elisabeth (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Lazaro Garcia, Conxi (Institut Català d'Oncologia)
Gel, Bernat (Universitat de Barcelona)
Carrió, Meritxell (Hereditary Cancer Group)
Serra, Eduard (Centro de Investigación Biomédica en Red de Cáncer)

Data:	2024
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI20/00228 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-496
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	JCI insight, Vol. 9 Núm. 3 (august 2024) , p. e168826, ISSN 2379-3708

DOI: 10.1172/jci.insight.168826
PMID: 38175707

19 p, 3.1 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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