Role of lysosome exocytosis in breast cancer progression

• Main Author: Sesifredo, Isabel de Sousa
• Publication Date: 2023
• Format: Master thesis
• Language: eng
• Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Download full: http://hdl.handle.net/10362/161446
• topic: Triple-negative breast cancer; lysosome exocytosis; Rab11; cell invasion; Ciências Médicas

Abstract Breast cancer (BC) is the most frequent type of cancer worldwide and the most common cause of cancer-related deaths in women. Among the subtypes, triplenegative BC (TNBC) displays the worst prognosis, a higher risk of relapse and metastasis formation, and limited treatment options. Therefore, it is crucial to unravel the mechanisms underlying TNBC cell invasion and metastasis formation to develop new therapies that block BC progression. Cancer cells subvert several pathways, including lysosome exocytosis, allowing them to acquire an aggressive phenotype. Lysosome exocytosis is important for plasma membrane repair, drug efflux, extracellular matrix degradation/remodeling, facilitating cell migration and invasion. Unpublished results from our group demonstrate an association between BC aggressiveness and lysosome exocytosis. Thus, this project aims to modulate lysosome exocytosis in TNBC cells, using different approaches, to impair BC progression. We found that the silencing of RAB11A/B in MDA-MB-231 cells impairs lysosome exocytosis, as previously shown by our group in HeLa cells. Additionally, RAB11A/B silencing lead to impaired cell invasion in MDA-MB-231 cells. However, only RAB11A depletion seems to inhibit cell migration, suggesting a dual role for RAB11A and RAB11B. In addition, RAB11 effector Sec15a/b and the interacting partner MyoH9 also seem to be involved in lysosome exocytosis. Furthermore, to confirm that lysosome exocytosis affects cell invasion, other regulators were investigated. Our results suggest that RAB3A and synaptotagmin VII might have a role in lysosome exocytosis in MDA-MB-231 cells. Finally, lysosome exocytosis inhibitors vacuolin-1 and verapamil were also tested. Interestingly, these compounds do not impair lysosome exocytosis in TNBC cells, contrary to what was observed in HeLa cells. Thus, other regulators and compounds that inhibit lysosome exocytosis, should be tested to confirm that lysosome exocytosis can indeed be targeted to impair TNBC progression. The knowledge obtained could be used to reduce or block of metastasis formation, increasing overall patient survival.