Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability.

E Martín-Villar,P Carrasco-Ramirez,M Quintanilla,G E Jones,B Borda-D'Agua,M Parsons,J Renart

doi:10.1038/onc.2014.388

Abstract

Invadopodia are actin-rich cell membrane projections used by invasive cells to penetrate the basement membrane. Control of invadopodia stability is critical for efficient degradation of the extracellular matrix (ECM); however, the underlying molecular mechanisms remain poorly understood. Here, we uncover a new role for podoplanin, a transmembrane glycoprotein closely associated with malignant progression of squamous cell carcinomas (SCCs), in the regulation of invadopodia-mediated matrix degradation. Podoplanin downregulation in SCC cells impairs invadopodia stability, thereby reducing the efficiency of ECM degradation. We report podoplanin as a novel component of invadopodia-associated adhesion rings, where it clusters prior to matrix degradation. Early podoplanin recruitment to invadopodia is dependent on lipid rafts, whereas ezrin/moesin proteins mediate podoplanin ring assembly. Finally, we demonstrate that podoplanin regulates invadopodia maturation by acting upstream of the ROCK-LIMK-Cofilin pathway through the control of RhoC GTPase activity. Thus, podoplanin has a key role in the regulation of invadopodia function in SCC cells, controlling the initial steps of cancer cell invasion.

Highlights

90% of human tumours arise from epithelial tissues, which are separated from the supporting stroma by the basement membrane (BM).[1]
Accumulating evidence demonstrates that cancer cells overcome the BM barrier by forming specialised F-actin-rich projections termed invadopodia, which serve as a localised source of matrix proteases and mediate the degradation of the extracellular matrix (ECM).[1,2,3]
To determine whether podoplanin pro-invasive properties could be related to invadopodia activity in squamous cell carcinomas (SCCs) cells, we first quantified the ability of the different cell lines to assemble invadopodia when plated on TRITC-gelatin

Summary

Introduction

90% of human tumours arise from epithelial tissues, which are separated from the supporting stroma by the basement membrane (BM).[1] Invasion of cancer cells through this physiological barrier represents a key step during cancer progression, because it is only within the supporting stroma that cancer cells gain access to the vascular and lymphatic systems and spread systemically. Despite current efforts to understand cancer cell invasion, the mechanisms underlying BM transmigration by tumour cells remain elusive. Accumulating evidence demonstrates that cancer cells overcome the BM barrier by forming specialised F-actin-rich projections termed invadopodia, which serve as a localised source of matrix proteases and mediate the degradation of the extracellular matrix (ECM).[1,2,3] A four-step model for invadopodia assembly has been defined revealing that stabilisation and complete maturation of invadopodia are required for efficient ECM degradation.[4,5,6] several studies have described their structural components,[7,8,9] there is a great interest in understanding the regulatory events controlling invadopodia stability and maturation.[10,11,12]

Methods

Results

Conclusion