{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:25:06Z","timestamp":1792013106969,"version":"4.4.0"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T00:00:00Z","timestamp":1707350400000},"content-version":"vor","delay-in-days":35,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Johns Hopkins University School of Medicine and the Neurofibromatosis Therapeutic Acceleration Program","award":["2003674057"],"award-info":[{"award-number":["2003674057"]}]},{"name":"Spanish Ministry of Science and Innovation, Carlos III Health Institute","award":["PI20\/00228"],"award-info":[{"award-number":["PI20\/00228"]}]},{"DOI":"10.13039\/501100002809","name":"Government of Catalonia","doi-asserted-by":"crossref","award":["2017-SGR-496"],"award-info":[{"award-number":["2017-SGR-496"]}],"id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,8]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>NF1<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    SCs and their interaction with the\n                    <jats:italic>NF1<\/jats:italic>\n                    <jats:sup>+\/\u2013<\/jats:sup>\n                    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\u2013coupled receptor 68 (\n                    <jats:italic>GPR68<\/jats:italic>\n                    ). 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\u2013derived 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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.168826","type":"journal-article","created":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T12:00:18Z","timestamp":1704369618000},"source":"Crossref","is-referenced-by-count":7,"title":["Unbalancing cAMP and Ras\/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas"],"prefix":"10.1172","volume":"9","author":[{"given":"Helena","family":"Mazuelas","sequence":"first","affiliation":[{"name":"Hereditary Cancer Group, Translational Cancer Research Program, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2741-4572","authenticated-orcid":true,"given":"Miriam","family":"Magall\u00f3n-Lorenz","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Group, Translational Cancer Research Program, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itziar","family":"Uriarte-Arrazola","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Group, Translational Cancer Research Program, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Negro","sequence":"additional","affiliation":[{"name":"Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain."},{"name":"Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inma","family":"Rosas","sequence":"additional","affiliation":[{"name":"Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain."},{"name":"Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Blanco","sequence":"additional","affiliation":[{"name":"Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain."},{"name":"Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Castellanos","sequence":"additional","affiliation":[{"name":"Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain."},{"name":"Genetics Service, Germans Trias i Pujol University Hospital, Can Ruti Campus, Badalona, Barcelona, 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