{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T02:34:00Z","timestamp":1773023640889,"version":"3.50.1"},"reference-count":70,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,25]],"date-time":"2023-06-25T00:00:00Z","timestamp":1687651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH","award":["813834"],"award-info":[{"award-number":["813834"]}]},{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH","award":["H2020-MSCA-ITN-2018"],"award-info":[{"award-number":["H2020-MSCA-ITN-2018"]}]},{"name":"European Marie Sk\u0142odowska-Curie Innovative Training Network (ITN) pH","award":["20174TB8KW002"],"award-info":[{"award-number":["20174TB8KW002"]}]},{"name":"Italian Ministry for Education, University and Research (MIUR)","award":["813834"],"award-info":[{"award-number":["813834"]}]},{"name":"Italian Ministry for Education, University and Research (MIUR)","award":["H2020-MSCA-ITN-2018"],"award-info":[{"award-number":["H2020-MSCA-ITN-2018"]}]},{"name":"Italian Ministry for Education, University and Research (MIUR)","award":["20174TB8KW002"],"award-info":[{"award-number":["20174TB8KW002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intracellular pH (pHi) regulation is a challenge for the exocrine pancreas, where the luminal secretion of bicarbonate-rich fluid is accompanied by interstitial flows of acid. This acid\u2013base transport requires a plethora of ion transporters, including bicarbonate transporters and the Na+\/H+ exchanger isoform 1 (NHE1), which are dysregulated in Pancreatic Ductal Adenocarcinoma (PDAC). PDAC progression is favored by a Collagen-I rich extracellular matrix (ECM) which exacerbates the physiological interstitial acidosis. In organotypic cultures of normal human pancreatic cells (HPDE), parenchymal cancer cells (CPCs) and cancer stem cells (CSCs) growing on matrices reproducing ECM changes during progression, we studied resting pHi, the pHi response to fluxes of NaHCO3 and acidosis and the role of NHE1 in pHi regulation. Our findings show that: (i) on the physiological ECM, HPDE cells have the most alkaline pHi, followed by CSCs and CPCs, while a Collagen I-rich ECM reverses the acid\u2013base balance in cancer cells compared to normal cells; (ii) both resting pHi and pHi recovery from an acid load are reduced by extracellular NaHCO3, especially in HPDE cells on a normal ECM; (iii) cancer cell NHE1 activity is less affected by NaHCO3. We conclude that ECM composition and the fluctuations of pHe cooperate to predispose pHi homeostasis towards the presence of NaHCO3 gradients similar to that expected in the tumor.<\/jats:p>","DOI":"10.3390\/ijms241310632","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T01:42:32Z","timestamp":1687743752000},"page":"10632","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ECM Composition Differentially Regulates Intracellular and Extracellular pH in Normal and Cancer Pancreatic Duct Epithelial Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Daria","family":"Di Molfetta","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy"}]},{"given":"Stefania","family":"Cannone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy"}]},{"given":"Maria Raffaella","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy"}]},{"given":"Rosa","family":"Caroppo","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 Bari, Italy"}]},{"given":"Francesca","family":"Piccapane","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnology and Environment, University of Bari Aldo Moro, 70126 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 Aldo Moro, 70126 Bari, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7306-9621","authenticated-orcid":false,"given":"Concetta","family":"Altamura","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}]},{"given":"Ilaria","family":"Saltarella","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy"}]},{"given":"Diana","family":"Tavares Valente","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8816-9369","authenticated-orcid":false,"given":"Jean Francois","family":"Desaphy","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari Aldo Moro, 70124 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 Aldo Moro, 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 Environment, University of Bari Aldo Moro, 70126 Bari, Italy"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,25]]},"reference":[{"key":"ref_1","unstructured":"Stark, A., and Eibl, G. 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