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GPER Activation Inhibits Cancer Cell Mechanotransduction and Basement Membrane Invasion via RhoA

1
Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Faculty of Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
2
Biozentrum and the Swiss Nanoscience Institute, University of Basel, 4056 Basel, Switzerland
3
Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK
4
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, 08003 Barcelona, Spain
5
School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the work.
Cancers 2020, 12(2), 289; https://doi.org/10.3390/cancers12020289
Received: 11 December 2019 / Revised: 15 January 2020 / Accepted: 17 January 2020 / Published: 25 January 2020
The invasive properties of cancer cells are intimately linked to their mechanical phenotype, which can be regulated by intracellular biochemical signalling. Cell contractility, induced by mechanotransduction of a stiff fibrotic matrix, and the epithelial–mesenchymal transition (EMT) promote invasion. Metastasis involves cells pushing through the basement membrane into the stroma—both of which are altered in composition with cancer progression. Agonists of the G protein-coupled oestrogen receptor (GPER), such as tamoxifen, have been largely used in the clinic, and interest in GPER, which is abundantly expressed in tissues, has greatly increased despite a lack of understanding regarding the mechanisms which promote its multiple effects. Here, we show that specific activation of GPER inhibits EMT, mechanotransduction and cell contractility in cancer cells via the GTPase Ras homolog family member A (RhoA). We further show that GPER activation inhibits invasion through an in vitro basement membrane mimic, similar in structure to the pancreatic basement membrane that we reveal as an asymmetric bilayer, which differs in composition between healthy and cancer patients.
Keywords: cancer biomechanics; metastasis; G protein-coupled receptors; tumour microenvironment cancer biomechanics; metastasis; G protein-coupled receptors; tumour microenvironment
MDPI and ACS Style

Rice, A.; Cortes, E.; Lachowski, D.; Oertle, P.; Matellan, C.; Thorpe, S.D.; Ghose, R.; Wang, H.; Lee, D.A.; Plodinec, M.; del Río Hernández, A.E. GPER Activation Inhibits Cancer Cell Mechanotransduction and Basement Membrane Invasion via RhoA. Cancers 2020, 12, 289.

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