Tumour cell blebbing and extracellular vesicle shedding: key role of matrikines and ribosomal protein SA

Bertrand Brassart,Mélissa Donet,Laurent Ramont,Aleksander Hinek,Christine Terryn,Fréderic Velard,Jean Michel,Sylvie Brassart-Pasco,Frédéric Hague,Emeline Seurat,Halima Ouadid-Ahidouch,Jean-Claude Monboisse,Jordan Da Silva,François-Xavier Maquart

doi:10.1038/s41416-019-0382-0

Abstract

BackgroundCarcinogenesis occurs in elastin-rich tissues and leads to local inflammation and elastolytic proteinase release. This contributes to bioactive matrix fragment (Matrikine) accumulation like elastin degradation products (EDP) stimulating tumour cell invasive and metastatic properties. We previously demonstrate that EDPs exert protumoural activities through Hsp90 secretion to stabilised extracellular proteinases.MethodsEDP influence on cancer cell blebbing and extracellular vesicle shedding were examined with a videomicroscope coupled with confocal Yokogawa spinning disk, by transmission electron microscopy, scanning electron microscopy and confocal microscopy. The ribosomal protein SA (RPSA) elastin receptor was identified after affinity chromatography by western blotting and cell immunolocalisation. mRNA expression was studied using real-time PCR. SiRNA were used to confirm the essential role of RPSA.ResultsWe demonstrate that extracellular matrix degradation products like EDPs induce tumour amoeboid phenotype with cell membrane blebbing and shedding of extracellular vesicle containing Hsp90 and proteinases in the extracellular space. EDPs influence intracellular calcium influx and cytoskeleton reorganisation. Among matrikines, VGVAPG and AGVPGLGVG peptides reproduced EDP effects through RPSA binding.ConclusionsOur data suggests that matrikines induce cancer cell blebbing and extracellular vesicle release through RPSA binding, favouring dissemination, cell-to-cell communication and growth of cancer cells in metastatic sites.

Highlights

Local invasion and metastasis of most malignant tumours require secretion of proteinases that degrade local extracellular matrix (ECM)
Electron microscopy analyses revealed cell morphology modifications induced by elastin degradation products (EDP) treatment
Cell blebbing capacity is correlated with Hsp[90] level We previously shown that EDPs stimulate Hsp[90] secretion in HT1080 fibrosarcoma and MDA-MB-231 breast carcinoma cells.[5]

Summary

Introduction

Local invasion and metastasis of most malignant tumours require secretion of proteinases that degrade local extracellular matrix (ECM). This process causes accumulation of ECM degradation products. Carcinogenesis occurs in elastin-rich tissues and leads to local inflammation and elastolytic proteinase release This contributes to bioactive matrix fragment (Matrikine) accumulation like elastin degradation products (EDP) stimulating tumour cell invasive and metastatic properties. RESULTS: We demonstrate that extracellular matrix degradation products like EDPs induce tumour amoeboid phenotype with cell membrane blebbing and shedding of extracellular vesicle containing Hsp[90] and proteinases in the extracellular space. CONCLUSIONS: Our data suggests that matrikines induce cancer cell blebbing and extracellular vesicle release through RPSA binding, favouring dissemination, cell-to-cell communication and growth of cancer cells in metastatic sites

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Conclusion