SCN4B acts as a metastasis-suppressor gene preventing hyperactivation of cell migration in breast cancer.

Émeline Bon ,Monique Anchelin,Frédéric Gradek,Isabelle Domingo,Séverine Marionneau-Lambot,Pierre Besson,Philippe G Frank,Thibauld Oullier,Sébastien Roger,Maria-Luisa Cayuela,Virginie Driffort,Roseline Guibon,Alain Moreau,Gaëlle Fromont,Stéphan Chevalier,Julien Burlaud‐Gaillard ,Pablo Pelegrı́n ,Éric Piver ,Jorge L Gutiérrez-Pajares ,Carlos Manuel Martínez-Cáceres

doi:10.1038/ncomms13648

Abstract

The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed ‘mesenchymal' and ‘amoeboid', with possible transitions between these modes. Here we show that the SCN4B gene, encoding for the β4 protein, initially characterized as an auxiliary subunit of voltage-gated sodium channels (NaV) in excitable tissues, is expressed in normal epithelial cells and that reduced β4 protein levels in breast cancer biopsies correlate with high-grade primary and metastatic tumours. In cancer cells, reducing β4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid–mesenchymal hybrid phenotype. This hyperactivated migration is independent of NaV and is prevented by overexpression of the intracellular C-terminus of β4. Conversely, SCN4B overexpression reduces cancer cell invasiveness and tumour progression, indicating that SCN4B/β4 represents a metastasis-suppressor gene.

Highlights

The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed ‘mesenchymal’ and ‘amoeboid’, with possible transitions between these modes
Expression of the b4 protein, encoded by the SCN4B gene[28], has mostly been studied in excitable cells in which mutations have been linked to sodium channelopathies[29,30]
Initial immunohistochemical analyses performed in normal and cancer breast tissues indicated that the SCN4B/b4 protein was expressed in epithelial cells from normal mammary acini, but was significantly downregulated in cancer cells (Fig. 1a,b)

Summary

Introduction

The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed ‘mesenchymal’ and ‘amoeboid’, with possible transitions between these modes. In cancer cells, reducing b4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid–mesenchymal hybrid phenotype. This hyperactivated migration is independent of NaV and is prevented by overexpression of the intracellular C-terminus of b4. In the ‘mesenchymal mode’, engaged cells harbour an elongated fibroblast-like morphology, with a rear-to-front lamellopodial cell polarity, and generate a path in the extracellular matrix (ECM) through proteolytic remodelling. In highly aggressive human breast cancer cells, the activity of pore-forming NaV1.5 is not associated with cell excitability but with ECM degradation and cancer cell invasiveness[21], favouring metastases development[22,23]. MNaoVd1u.l5a-tdioenpenodfentht einNvaasþiv–enHesþs is mediated through allosteric exchanger NHE1, subsequent acidification of the pericellular microenvironment and activation of extracellular acidic cysteine cathepsins[24,25,26]

Methods

Results

Conclusion