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Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH and Ion Transport in Pancreatic Cancer\u2013pHioniC","award":["UIDB\/50026\/2020"],"award-info":[{"award-number":["UIDB\/50026\/2020"]}]},{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH and Ion Transport in Pancreatic Cancer\u2013pHioniC","award":["UIDP\/50026\/2020"],"award-info":[{"award-number":["UIDP\/50026\/2020"]}]},{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH and Ion Transport in Pancreatic Cancer\u2013pHioniC","award":["NORTE-01-0145-FEDER-000055"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000055"]}]},{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH and Ion Transport in Pancreatic Cancer\u2013pHioniC","award":["SFRH\/BD\/103025\/2014"],"award-info":[{"award-number":["SFRH\/BD\/103025\/2014"]}]},{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH and Ion Transport in Pancreatic Cancer\u2013pHioniC","award":["813834"],"award-info":[{"award-number":["813834"]}]},{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH and Ion Transport in Pancreatic Cancer\u2013pHioniC","award":["H2020-MSCA-ITN-2018"],"award-info":[{"award-number":["H2020-MSCA-ITN-2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.<\/jats:p>","DOI":"10.3390\/cancers15153868","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T01:48:50Z","timestamp":1690768130000},"page":"3868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9367-5979","authenticated-orcid":false,"given":"Diana","family":"Tavares-Valente","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Braga, Portugal"},{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"given":"Stefania","family":"Cannone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"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\/0000-0001-9095-1413","authenticated-orcid":false,"given":"Tiago Miguel Amaral","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1770-4544","authenticated-orcid":false,"given":"F\u00e1tima","family":"Baltazar","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4805-017 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5912-3409","authenticated-orcid":false,"given":"Od\u00edlia","family":"Queir\u00f3s","sequence":"additional","affiliation":[{"name":"UNIPRO\u2014Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5219-4412","authenticated-orcid":false,"given":"Gennaro","family":"Agrimi","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari, 70125 Bari, Italy"}]},{"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":[[2023,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2021","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. 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