Influence of hypoxic extracellular vesicles in cell invasion and tumour microenvironment on Breast Cancer

Abstract

Extracellular Vesicles (EV) are structures able to carry biomolecules stably, whose function is mainly of cell-cell communication. During Cancer development, the establishment of hypoxia stimulates the secretion of tumour derived EVs, which will act in all the steps of the metastatic cascade, especially in the communication between cells of the Tumour Microenvironment (TME). Signalling from the TME is essential to the triggering of cell invasion, a behaviour in which cells detach from the primary tumour, acquire a mesenchymal phenotype and invade the adjacent tissues, in search of a new metastatic niche. In order to understand the biological and molecular role of tumour-SEV secreted in hypoxia on the invasion of triple-negative Breast Cancer cells, we shall investigate the influence of the tumour microenvironment in this process. Our study intends to enlighten, using biomolecule large-scale analyses, some of the molecular mechanisms involved in hypoxic-SEV-mediated invasion in cells from the tumour microenvironment. We propose the use of three cell lines (MDA-MB-231, THP-1 and HF), which will be submitted to cellular, biochemical and molecular techniques for global analysis of protein, lipid, mRNA and metabolite. Early results indicate a pro-invasive action of hypoxic-SEV in Breast Cancer cell invasion that is gelatinase (MMP-2 and MMP-9)-independent. We expect to detect robust changes in protein, lipid, mRNA and metabolite profile in cells from the tumour microenvironment upon hypoxic-SEV treatment thus favouring its pro-tumoral role. The results obtained in this project aim to discover new targets for future therapeutic applications in highly metastatic breast tumours. (AU)