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Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells
Tishchenko, Alexander (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Azorín, Daniel D. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Vidal-Brime, Laia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
José Muñoz, María (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Jiménez Arenas, Pol (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Pearce, Christopher (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Girao, Henrique (University of Coimbra. Faculty of Medicine)
Ramón y Cajal, Santiago (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Aasen, Trond (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Date: 2020
Abstract: 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.
Note: Altres ajuts: A. acknowledges funding from Fundación Científica Asociación Española Contra el Cáncer (IDEAS SEMILLA AECC 2020/IDEAS20033PUIG) and Instituto de Salud Carlos III co-financed by the European Regional Development Fund (ERDF) . The APC was funded by Instituto de Salud Carlos III co-financed by the European Regional Development Fund (ERDF). H.G is funded by the European Regional Development Fund (ERDF) through the Operational Program for Competitiveness Factors (COMPETE; under the projects PAC "NETDIAMOND" POCI-01-0145-FEDER-016385; HealthyAging2020 CENTRO-01-0145-FEDER-000012-N2323; POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-032179, CENTRO-01-0145-FEDER-032414, POCI-01-0145-FEDER-022122, FCTUID/NEU/04539/2013, UID/NEU/04539/2019, UIDB/04539/2020 and UIDP/04539/2020.
Note: Número d'acord de subvenció ISCIII/PI16-00772
Note: Número d'acord de subvenció ISCIII/CPII16-00042
Note: Número d'acord de subvenció ISCIII/PI16-00772
Rights: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Language: Anglès
Document: article ; recerca ; publishedVersion
Subject: Connexin 43 ; Gap junctions ; Cancer ; Intercellular communication ; Breast cancer ; Cell signaling ; Tunneling nanotubes ; Cell-cell communication ; Tumor microtubes
Published in: Cancers, Vol. 12 Núm. 10 (2020) , p. 2798, ISSN 2072-6694

DOI: 10.3390/cancers12102798
PMID: 33003486


25 p, 4.2 MB

The record appears in these collections:
Articles > Research articles
Articles > Published articles

 Record created 2020-11-11, last modified 2021-02-20



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