{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T07:05:39Z","timestamp":1779692739963,"version":"3.53.1"},"reference-count":97,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Project PRIN 2022","award":["20227YTZE3"],"award-info":[{"award-number":["20227YTZE3"]}]},{"name":"PRIN 2022 PNRR","award":["P2022L5HAZ"],"award-info":[{"award-number":["P2022L5HAZ"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Vasculogenic mimicry (VM) is the ability of cancer stem cells (CSCs) to express an endothelial-like phenotype and participate in tumor neovascularization via the formation of a blood-conducting, matrix-rich network. We previously reported that pancreatic ductal adenocarcinoma (PDAC) CSCs develop their VM phenotype via two interacting and coordinated factors that support the formation of the VM network: (i) the overexpression of genes for endothelial factors and vascular receptors and (ii) the very high secretion of numerous pro-angiogenic\/growth factors. While microenvironmental acidosis (low pHe) is an important driver of tumor metastasis, especially in PDAC, and is a component of the CSC niche, its role in VM and the ion transporters involved remains unknown. As normal stem cell differentiation is regulated by Na+\/H+ exchanger 1 (NHE1)-driven pH, we investigated the role of NHE1 and the intracellular signaling involved in the acidosis-induced VM using a platform of 3D organotypic cultures composed of Matrigel with increasing concentrations of Collagen I. VM was highest on 90% Matrigel:10% Collagen I, representative of an early tumor ECM, and it decreased with increasing concentrations of Collagen I, representative of advanced tumors. In all ECM compositions, VM capacity increased stepwise with pHe acidification, and both basal and acid-stimulated VM were dependent on NHE1 activity. Acidification also decreased resting pHi and increased NHE1 proton extrusion activity, NHE1\/\u00df1 integrin co-expression, and intracellular Ca2+. The stimulation of VM by extracellular acidosis depended on the transport of extracellular Ca2+ into the cell and the consequent increase in intracellular Ca2+. Altogether, these data demonstrate that extracellular acidification triggers cellular mechanisms that upregulate VM to overcome the constraints imposed by ECM composition, thereby permitting VM in ECMs where this phenotype is not expressed and extending the VM phenotype towards the tumor center to further drive metastasis.<\/jats:p>","DOI":"10.3390\/cells15100865","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:42:18Z","timestamp":1779691338000},"page":"865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acidosis Drives Vasculogenic Mimicry in PDAC CSCs via Na+\/H+ Exchanger Isoform 1 (NHE1) and Calcium Entry"],"prefix":"10.3390","volume":"15","author":[{"given":"Maria Raffaella","family":"Greco","sequence":"first","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Fracasso","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Cannone","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4696-9944","authenticated-orcid":false,"given":"Daria","family":"Di Molfetta","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4233-9920","authenticated-orcid":false,"given":"Marilena","family":"Ardone","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8488-440X","authenticated-orcid":false,"given":"Sharon Natasha","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brunella Rita","family":"Ladogana","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6303-0969","authenticated-orcid":false,"given":"Daniela Isabel","family":"Abbrescia","sequence":"additional","affiliation":[{"name":"CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council (CNR), Via G. Amendola 122\/0, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5081-4745","authenticated-orcid":false,"given":"Apollonia","family":"Tullo","sequence":"additional","affiliation":[{"name":"CNR Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council (CNR), Via G. Amendola 122\/0, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3118-5813","authenticated-orcid":false,"given":"Marianna","family":"Ranieri","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9757-5908","authenticated-orcid":false,"given":"Stephan J.","family":"Reshkin","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2011-9135","authenticated-orcid":false,"given":"Rosa Angela","family":"Cardone","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona 4, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1002\/med.21765","article-title":"Understanding the tumor microenvironment for effective immunotherapy","volume":"41","author":"Rad","year":"2021","journal-title":"Med. Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bo\u017cyk, A., Wojas-Krawczyk, K., Krawczyk, P., and Milanowski, J. (2022). Tumor Microenvironment\u2014A Short Review of Cellular and Interaction Diversity. 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