{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:39:37Z","timestamp":1790627977835,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T00:00:00Z","timestamp":1620777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014732","name":"Neurofibromatosis Therapy Acceleration Program","doi-asserted-by":"publisher","award":["10 80028823"],"award-info":[{"award-number":["10 80028823"]}],"id":[{"id":"10.13039\/100014732","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Plexiform neurofibromas (Pnfs) are benign peripheral nerve sheath tumors that are major features of the human genetic syndrome, neurofibromatosis type 1 (NF1). Pnfs are derived from Schwann cells (SCs) undergoing loss of heterozygosity (LOH) at the NF1 locus in an NF1+\/\u2212 milieu and thus are variably lacking in the key Ras-controlling protein, neurofibromin (Nfn). As these SCs are embedded in a dense desmoplastic milieu of stromal cells and abnormal extracellular matrix (ECM), cell\u2013cell cooperativity (CCC) and the molecular microenvironment play essential roles in Pnf progression towards a malignant peripheral nerve sheath tumor (MPNST). The complexity of Pnf biology makes treatment challenging. The only approved drug, the MEK inhibitor Selumetinib, displays a variable and partial therapeutic response. Here, we explored ECM contributions to the growth of cells lacking Nfn. In a 3D in vitro culture, NF1 loss sensitizes cells to signals from a Pnf-mimicking ECM through focal adhesion kinase (FAK) hyperactivation. This hyperactivation correlated with phosphorylation of the downstream effectors, Src, ERK, and AKT, and with colony formation. Expression of the GAP-related domain of Nfn only partially decreased activation of this signaling pathway and only slowed down 3D colony growth of cells lacking Nfn. However, combinatorial treatment with both the FAK inhibitor Defactinib (VS-6063) and Selumetinib (AZD6244) fully suppressed colony growth. These observations pave the way for a new combined therapeutic strategy simultaneously interfering with both intracellular signals and the interplay between the various tumor cells and the ECM.<\/jats:p>","DOI":"10.3390\/cancers13102329","type":"journal-article","created":{"date-parts":[[2021,5,12]],"date-time":"2021-05-12T10:59:12Z","timestamp":1620817152000},"page":"2329","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Neurofibromin Deficiency and Extracellular Matrix Cooperate to Increase Transforming Potential through FAK-Dependent Signaling"],"prefix":"10.3390","volume":"13","author":[{"given":"Andrea","family":"Errico","sequence":"first","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3781-6954","authenticated-orcid":false,"given":"Anna","family":"Stocco","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent M.","family":"Riccardi","sequence":"additional","affiliation":[{"name":"The Neurofibromatosis Institute, La Crescenta, CA 91914, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Gambalunga","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Bassetto","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Grigatti","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amedeo","family":"Ferlosio","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Tadini","sequence":"additional","affiliation":[{"name":"Center for Inherited Cutaneous Diseases, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Garozzo","sequence":"additional","affiliation":[{"name":"Mediclinic Parkview Hospital, Dubai, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2688-4660","authenticated-orcid":false,"given":"Stefano","family":"Ferraresi","sequence":"additional","affiliation":[{"name":"Ospedale S. Maria della Misericordia, Divisione di Neurochirurgia, 45100 Rovigo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0764-1084","authenticated-orcid":false,"given":"Andrea","family":"Trevisan","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7034-3816","authenticated-orcid":false,"given":"Sandra","family":"Giustini","sequence":"additional","affiliation":[{"name":"Department of Clinical, Anesthesiologic and Cardio-Vascular Sciences, University of Sapienza, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4522-3008","authenticated-orcid":false,"given":"Andrea","family":"Rasola","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2396-3080","authenticated-orcid":false,"given":"Federica","family":"Chiara","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E8","DOI":"10.3171\/2009.11.FOCUS09221","article-title":"Neurofibromatosis Type 1 and tumorigenesis: Molecular mechanisms and therapeutic implications","volume":"28","author":"Gottfried","year":"2010","journal-title":"Neurosurg. 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