{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:59:43Z","timestamp":1760147983023,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,16]],"date-time":"2023-03-16T00:00:00Z","timestamp":1678924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero dell\u2019Istruzione dell\u2019Universit\u00e0 e della Ricerca","award":["PRIN 2017-Prot. 20174TB8KW"],"award-info":[{"award-number":["PRIN 2017-Prot. 20174TB8KW"]}]},{"name":"\u201cSapienza\u201d, University of Rome, Italy","award":["PRIN 2017-Prot. 20174TB8KW"],"award-info":[{"award-number":["PRIN 2017-Prot. 20174TB8KW"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Actinic keratosis (AK) is a preneoplastic skin disorder which can rapidly progress to cutaneous squamous cell carcinomas (SCCs). In light of our previous findings, indicating a possible oncogenic role of the mesenchymal isoform of FGFR2 (FGFR2c) aberrantly expressed in AK keratinocytes, we analyzed the possible tumor-promoting role of this receptor in the stromal AK counterpart in this work. Molecular analysis showed that, particularly in early AK lesions, FGFR2c dermal upregulation is accompanied by the downregulation of the cancer-associated fibroblasts (CAF) transcription repressor CSL, the upregulation of the CAF activator ULK3, and the consequent CAF gene induction. Immunofluorescence and molecular analysis, coupled with silencing approaches by siRNA, applied on primary cultures of KIN I-derived fibroblasts, indicated that FGFR2c upregulation contribute to CAF signature and the increased autophagy in response to FGF2. Magnetic bead-based multiplex assay, combined with FGFR2 signaling shut-off approaches, indicated that, especially in response to FGF2, IL-6 secretion could depend on FGFR2c high expression and signaling, suggesting the possible establishment of FGFR2c-dependent secretory autophagy, contributing to tumor-promoting factor release. Overall, our results identified FGFR2c as a signaling molecule involved in controlling precancerous\/stromal cell oncogenic crosstalk, pointing to this receptor as a possible early molecular marker predictive for AK\u2019s rapid malignant progression.<\/jats:p>","DOI":"10.3390\/biology12030463","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T02:59:26Z","timestamp":1679021966000},"page":"463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["FGFR2c Upregulation Contributes to Cancer-Associated Fibroblast Program Activation and to Enhanced Autophagy in Actinic Keratosis-Derived Dermal Fibroblasts: A Possible Role in Precancerous Cell\/Stromal Cell Crosstalk"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4182-1633","authenticated-orcid":false,"given":"Luisa","family":"Guttieri","sequence":"first","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9501-7638","authenticated-orcid":false,"given":"Salvatore","family":"Raffa","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"},{"name":"Laboratory of Ultrastructural Pathology, Unit of Medical Genetics and Advanced Cellular Diagnostics, Department of Diagnostic Sciences, Sant\u2019Andrea University Hospital, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6597-1452","authenticated-orcid":false,"given":"Gerardo","family":"Salerno","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, 00161 Rome, Italy"},{"name":"Laboratory of Clinical Chemistry, Sant\u2019Andrea University Hospital, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachele","family":"Bigi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia","family":"Persechino","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5067-3121","authenticated-orcid":false,"given":"Vincenzo","family":"Visco","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"},{"name":"Laboratory of Ultrastructural Pathology, Unit of Medical Genetics and Advanced Cellular Diagnostics, Department of Diagnostic Sciences, Sant\u2019Andrea University Hospital, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Rosaria","family":"Torrisi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danilo","family":"Ranieri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Belleudi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1365-2133.2007.07860.x","article-title":"Actinic keratosis is an early in situ squamous cell carcinoma: A proposal for reclassification","volume":"156","author":"Patel","year":"2007","journal-title":"Br. 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