{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T17:57:30Z","timestamp":1775066250959,"version":"3.50.1"},"reference-count":121,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T00:00:00Z","timestamp":1601337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["PI16\/00772; CPII16\/00042"],"award-info":[{"award-number":["PI16\/00772; CPII16\/00042"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI16\/00772; CPII16\/00042"],"award-info":[{"award-number":["PI16\/00772; CPII16\/00042"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer","doi-asserted-by":"publisher","award":["Ideas Semillas 2020"],"award-info":[{"award-number":["Ideas Semillas 2020"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR\/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.<\/jats:p>","DOI":"10.3390\/cancers12102798","type":"journal-article","created":{"date-parts":[[2020,9,29]],"date-time":"2020-09-29T08:43:27Z","timestamp":1601369007000},"page":"2798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Alexander","family":"Tishchenko","sequence":"first","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}]},{"given":"Daniel D.","family":"Azor\u00edn","sequence":"additional","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}]},{"given":"Laia","family":"Vidal-Brime","sequence":"additional","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}]},{"given":"Mar\u00eda Jos\u00e9","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}]},{"given":"Pol Jim\u00e9nez","family":"Arenas","sequence":"additional","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}]},{"given":"Christopher","family":"Pearce","sequence":"additional","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5786-8447","authenticated-orcid":false,"given":"Henrique","family":"Girao","sequence":"additional","affiliation":[{"name":"Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal"},{"name":"Center for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal"},{"name":"Clinical Academic Centre of Coimbra, CACC, 3000-548 Coimbra, Portugal"}]},{"given":"Santiago","family":"Ram\u00f3n y Cajal","sequence":"additional","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"Anatom\u00eda Patol\u00f3gica, Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"CIBER de C\u00e1ncer (CIBERONC), Instituto de Salud Carlos III, Avenida de Monforte de Lemos 3-5, 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0763-2695","authenticated-orcid":false,"given":"Trond","family":"Aasen","sequence":"additional","affiliation":[{"name":"Patologia Molecular Translacional, Vall d\u2019Hebron Institut de Recerca (VHIR), Vall d\u2019Hebron Hospital Universitari, Vall d\u2019Hebron Barcelona Hospital Campus, Passeig Vall d\u2019Hebron 119-129, 08035 Barcelona, Spain"},{"name":"CIBER de C\u00e1ncer (CIBERONC), Instituto de Salud Carlos III, Avenida de Monforte de Lemos 3-5, 28029 Madrid, Spain"},{"name":"Universitat Aut\u00f2noma de Barcelona, 08193 Bellaterra, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Aasen, T., Johnstone, S., Vidal-Brime, L., Lynn, K.S., and Koval, M. 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