Extracellular protonation modulates cell-cell interaction mechanics and tissue invasion in human melanoma cells

Detachment of cells from the primary tumour precedes metastatic progression by facilitating cell release into the tissue. Solid tumours exhibit altered pH homeostasis with extracellular acidification. In human melanoma, the Na+/H+ exchanger NHE1 is an important modifier of the tumour nanoenvironment...

Authors: Hofschröer, Verena
Koch, Kevin Alexander
Ludwig, Florian Timo
Friedl, Peter
Oberleithner, Hans
Stock, Christian
Schwab, Albrecht
Division/Institute:FB 05: Medizinische Fakultät
Document types:Article
Media types:Text
Publication date:2017
Date of publication on miami:16.03.2018
Modification date:16.04.2019
Edition statement:[Electronic ed.]
Source:Scientific Reports 7 (2017) 42369, 1-13
DDC Subject:610: Medizin und Gesundheit
License:CC BY 4.0
Language:English
Funding:Finanziert durch den Open-Access-Publikationsfonds 2017 der Westfälischen Wilhelms-Universität Münster (WWU Münster).
Format:PDF document
URN:urn:nbn:de:hbz:6-59129524259
Permalink:http://nbn-resolving.de/urn:nbn:de:hbz:6-59129524259
Other Identifiers:DOI: 10.1038/srep42369
Digital documents:srep42369.pdf

Detachment of cells from the primary tumour precedes metastatic progression by facilitating cell release into the tissue. Solid tumours exhibit altered pH homeostasis with extracellular acidification. In human melanoma, the Na+/H+ exchanger NHE1 is an important modifier of the tumour nanoenvironment. Here we tested the modulation of cell-cell-adhesion by extracellular pH and NHE1. MV3 tumour spheroids embedded in a collagen matrix unravelled the efficacy of cell-cell contact loosening and 3D emigration into an environment mimicking physiological confinement. Adhesive interaction strength between individual MV3 cells was quantified using atomic force microscopy and validated by multicellular aggregation assays. Extracellular acidification from pHe7.4 to 6.4 decreases cell migration and invasion but increases single cell detachment from the spheroids. Acidification and NHE1 overexpression both reduce cell-cell adhesion strength, indicated by reduced maximum pulling forces and adhesion energies. Multicellular aggregation and spheroid formation are strongly impaired under acidification or NHE1 overexpression. We show a clear dependence of melanoma cell-cell adhesion on pHe and NHE1 as a modulator. These effects are opposite to cell-matrix interactions that are strengthened by protons extruded via NHE1. We conclude that these opposite effects of NHE1 act synergistically during the metastatic cascade.