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All these factors are favored by its extracellular matrix (ECM)-rich microenvironment, which is also highly hypoxic and acidic. Gemcitabine (GEM) is still the first-line therapy in PDAC. However, it is quickly deaminated to its inactive metabolite. Several GEM prodrugs have emerged to improve its cytotoxicity. Here, we analyzed how the acidic\/hypoxic tumor microenvironment (TME) affects the response of PDAC cell death and invadopodia-mediated ECM proteolysis to both GEM and its C18 prodrug. Methods: For this, two PDAC cell lines, PANC-1 and Mia PaCa-2 were adapted to pHe 6.6 or not for 1 month, grown as 3D organotypic cultures and exposed to either GEM or C18 in the presence and absence of acidosis and the hypoxia inducer, deferoxamine. Results: We found that C18 has higher cytotoxic and anti-invadopodia activity than GEM in all culture conditions and especially in acid and hypoxic environments. Conclusions: We propose C18 as a more effective approach to conventional GEM in developing new therapeutic strategies overcoming PDAC chemoresistance.<\/jats:p>","DOI":"10.3390\/cells13090730","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T10:34:05Z","timestamp":1713868445000},"page":"730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tumor Microenvironment Modulates Invadopodia Activity of Non-Selected and Acid-Selected Pancreatic Cancer Cells and Its Sensitivity to Gemcitabine and C18-Gemcitabine"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-1413","authenticated-orcid":false,"given":"Tiago M. A.","family":"Carvalho","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-1481","authenticated-orcid":false,"given":"Madelaine Magal\u00ec","family":"Audero","sequence":"additional","affiliation":[{"name":"U1003 PHYCEL Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, 59000 Lille, France"}]},{"given":"Maria Raffaella","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4233-9920","authenticated-orcid":false,"given":"Marilena","family":"Ardone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"given":"Teresa","family":"Maggi","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5966-5064","authenticated-orcid":false,"given":"Rosanna","family":"Mallamaci","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6138-1503","authenticated-orcid":false,"given":"Barbara","family":"Rolando","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4754-6591","authenticated-orcid":false,"given":"Silvia","family":"Arpicco","sequence":"additional","affiliation":[{"name":"Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3084-0380","authenticated-orcid":false,"given":"Federico Alessandro","family":"Ruffinatti","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4576-1594","authenticated-orcid":false,"given":"Alessandra Fiorio","family":"Pla","sequence":"additional","affiliation":[{"name":"U1003 PHYCEL Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, 59000 Lille, France"},{"name":"Laboratory of Cellular and Molecular Angiogenesis, Department of Life Sciences and Systems Biology, University of Turin, 10123 Turin, Italy"}]},{"given":"Natalia","family":"Prevarskaya","sequence":"additional","affiliation":[{"name":"U1003 PHYCEL Laboratoire de Physiologie Cellulaire, Inserm, University of Lille, 59000 Lille, France"}]},{"given":"Tomas","family":"Koltai","sequence":"additional","affiliation":[{"name":"Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9757-5908","authenticated-orcid":false,"given":"Stephan J.","family":"Reshkin","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 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 Environment, University of Bari, 70125 Bari, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ejca.2019.11.002","article-title":"Nationwide trends in incidence, treatment and survival of pancreatic ductal adenocarcinoma","volume":"125","author":"Latenstein","year":"2020","journal-title":"Eur. 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