Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas

• DOI: 10.1172/jci.insight.168826
• Publication Date: 2024-01-04T17:00:18Z
• Authors: Helena Mazuelas; Miriam Magallón-L...; Itziar Uriarte-Ar...; Alejandro Negro; Inma Rosas; Ignacio Blanco; Elisabeth Castell...; Conxi Lázaro; Bernat Gel; Meritxell Carrió; Eduard Serra
• Keywords: 0301 basic medicine; Cytogenetics; 0303 health sciences; 03 medical and health sciences; Citogenètica; Càncer; Cancer; Research Article; 3. Good health

AbstractCutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Neurofibromatosis Type 1 (NF1) individuals may develop thousands of cNFs, greatly affecting their quality of life. cNF growth is governed by the proliferation ofNF1(-/-) SCs, highly influenced by the interaction with aNF1(+/-) microenvironment, consisting of fibroblasts (FBs), immune cells, etc. To decompose crosstalk between SCs and the microenvironment we used single cultures and co-cultures of cNF-derived SCs and FBs and identified an expression signature specific to SC-FB interaction. This signature was enriched in genes involved in immune cell migration, that were functionally validated by secretion analysis of SC-FB co-cultures, suggesting a role of SC-FB crosstalk in immune cell recruitment. The signature also captured components of different developmental signaling pathways, among them, the cAMP elevator G protein-coupled receptor 68 (GPR68). Activation of Gpr68 by Ogerin reduced the viability and proliferation of cNF-derived SCs and SC-FB co-cultures. Moreover, Ogerin in combination with the MEKi Selumetinib induced loss of viability, SC differentiation, and death. These results were corroborated using an iPSC-derived 3D neurofibromasphere model. The unbalancing of the Ras and cAMP pathways by combining a MEKi and a cAMP elevator arises as a potential treatment for cNFs.