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MCA-ITN-2018","award":["813834"],"award-info":[{"award-number":["813834"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of all cancers, having one of the lowest five-year survival rates. One of its hallmarks is a dense desmoplastic stroma consisting in the abnormal accumulation of extracellular matrix (ECM) components, especially Collagen I. This highly fibrotic stroma embeds the bulk cancer (parenchymal) cells (CPCs), cancer stem cells (CSCs) and the main producers of the stromal reaction, the Cancer Associated Fibroblasts (CAFs). Little is known about the role of the acellular ECM in the interplay of the CAFs with the different tumor cell types in determining their phenotypic plasticity and eventual cell fate. Methods: Here, we analyzed the role of ECM collagen I in modulating the effect of CAF-derived signals by incubating PDAC CPCs and CSCs grown on ECM mimicking early (low collagen I levels) and late (high collagen I levels) stage PDAC stroma with conditioned medium from primary cultured CAFs derived from patients with PDAC in a previously described three-dimensional (3D) organotypic model of PDAC. Results: We found that CAFs (1) reduced CPC growth while favoring CSC growth independently of the ECM; (2) increased the invasive capacity of only CPCs on the ECM mimicking the early tumor; and (3) favored vasculogenic mimicry (VM) especially of the CSCs on the ECM mimicking an early tumor. Conclusions: We conclude that the CAFs and acellular stromal components interact to modulate the tumor behaviors of the PDAC CPC and CSC cell types and drive metastatic progression by stimulating the phenotypic characteristics of each tumor cell type that contribute to metastasis.<\/jats:p>","DOI":"10.3390\/cancers14153737","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T21:49:02Z","timestamp":1659304142000},"page":"3737","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Cancer Associated Fibroblast (CAF) Regulation of PDAC Parenchymal (CPC) and CSC Phenotypes Is Modulated by ECM Composition"],"prefix":"10.3390","volume":"14","author":[{"given":"Stefania","family":"Cannone","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"given":"Maria Raffaella","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-1413","authenticated-orcid":false,"given":"Tiago M. A.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"given":"Helene","family":"Guizouarn","sequence":"additional","affiliation":[{"name":"Institute of Biology de Valrose, CNRS UMR 7277, University of Nice, 06108 Nice, France"}]},{"given":"Olivier","family":"Soriani","sequence":"additional","affiliation":[{"name":"Institute of Biology de Valrose, CNRS UMR 7277, University of Nice, 06108 Nice, France"}]},{"given":"Daria","family":"Di Molfetta","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0869-0811","authenticated-orcid":false,"given":"Richard","family":"Tomasini","sequence":"additional","affiliation":[{"name":"INSERM, U1068, Centre de Recherche en Canc\u00e9rologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, 13009 Marseille, France"}]},{"given":"Katrine","family":"Zeeberg","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9757-5908","authenticated-orcid":false,"given":"Stephan Joel","family":"Reshkin","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2011-9135","authenticated-orcid":false,"given":"Rosa Angela","family":"Cardone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"716","DOI":"10.5858\/2010-0566-RA.1","article-title":"Molecular signatures of pancreatic cancer","volume":"135","author":"Hong","year":"2011","journal-title":"Arch. 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Biol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/15\/3737\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:00:29Z","timestamp":1760140829000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/15\/3737"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,31]]},"references-count":42,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["cancers14153737"],"URL":"https:\/\/doi.org\/10.3390\/cancers14153737","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,31]]}}}