Session: Session 2

ROLE OF EXTRACELLULAR VESICLES IN THE BRAIN METASTASIS TROPISM OF TRIPLE NEGATIVE BREAST CANCER

Triple-negative breast cancer (TNBC) is considered as the most aggressive and metastatic subtype. It exhibits metastases in preferential target organs: bones, lungs, liver, and brain. However, chemoresistance is leading to an alarming increase in brain tropism which represents a major cause of death due to the challenging of their treatment. The spread of tumor cells is a non-random process because it requires the preparation of a pre-metastatic niche (PMN). The underlying molecular mechanisms involved in the conditioning of PMN and the messengers delivered in return to recruit tumor cells, are not well described. Recent studies suggest the importance of extracellular vesicles (EVs) in this molecular communication. EVs (exosomes and microvesicles) are important messengers by carrying biological signals at distance (proteins, lipids and nucleic acids). By using a large scale proteomic approach, this project aims to understand the molecular mechanisms involving EVs derived from primary TNBC cells, in the targeting of potential PMN in brain. Proteins on surface of EVs play an important role in docking with target cells at a specific secondary site during the PMN. EVs from a parental cell line of human TNBC (MDA-MB-231-TGL) were compared to those of its derivative brain metastatic cell line (MDA-BrM2-831), established after the injection of the parental cell line in nude mice and the collection of metastatic clones in brain. The characterization of surface and intravesicular proteins aim to better understand specific changes in EV subtypes to establish PMN in brain. EVs were used to challenge astrocytes and microglia and investigate the subsequent protein changes and secretomes. The first results suggested the production of differential EV surfaceomes. Moreover, some molecules in astrocytes, known to promote brain metastasis were upregulated by EVs derived from MDA-BrM2-831. The specific inhibition of EV surfaceomes would give a new insight into the PMN physiopathology.