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

Mazuelas, H.; Magallon-Lorenz, M.; Uriarte-Arrazola, I.; Negro, A.; Rosas, I.; Blanco, I.; Castellanos, E.; Lazaro, C.; Gel Moreno, B.; Carrio, M.; Serra, E.

doi:10.1101/2022.12.23.521754

bioRxiv · 10.1101/2022.12.23.521754

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

Mazuelas, H.·Magallon-Lorenz, M.·Uriarte-Arrazola, I.·Negro, A.·Rosas, I.·Blanco, I.·Castellanos, E.·Lazaro, C.·Gel Moreno, B.·Carrio, M.·Serra, E.

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Abstract

Cutaneous 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 of NF1(-/-) SCs, highly influenced by the interaction with a NF1(+/-) 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.

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Mazuelas, H., Magallon-Lorenz, M., Uriarte-Arrazola, I., Negro, A., Rosas, I., Blanco, I., Castellanos, E., Lazaro, C., Gel Moreno, B., Carrio, M., Serra, E.. 2022-12-23. Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas. https://doi.org/10.1101/2022.12.23.521754

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