[iNOVA4Health] Regulated lysosomal exocytosis, an unconventional pathway in cancer progression

iNOVA4Health Seminar

Title: Regulated lysosomal exocytosis, an unconventional pathway in cancer progression

Speaker: Eda Machado

Affiliation: St. Jude Children's Research Hospital, Memphis, Memphis, Tennessee USA (ITQB NOVA ALUMNI)

Host: Catarina Brito Lab - Advanced Cell Models

Abstract:

How do cancer cells transition to an invasive, metastatic and drug resistant state is still unclear. We unraveled lysosomal exocytosis as an unconventional cellular process at the basis of cancer progression, which is regulated by the lysosomal sialidase NEU1. Loss of NEU1 function leads to the accumulation of an oversialylated LAMP1, a substrate of NEU1, at the lysosomal membrane. This topological change increases the number of lysosomes docked at the plasma membrane, poised to engage in lysosomal exocytosis upon calcium-influx. The ensuing excessive release of lysosomal contents results in abnormal degradation of the extracellular matrix (ECM), facilitates tumor cells’ migration and invasion, and renders them resistant to drugs that are lysosomotropic and hence preferentially sequestered in acidic lysosomes. We found that Neu1 haploinsufficiency in a tumor prone mouse model was sufficient to induce the development of aggressive and rare forms of pleomorphic sarcomas, which resembles pleomorphic, metastatic human sarcomas, with low NEU1 expression. Most importantly, these malignant phenotypic features of sarcomas could be reverted by targeting initiators or effectors of lysosomal exocytosis, i.e. increasing NEU1 levels or silencing LAMP1. Thus, lysosomal exocytosis could be exploited for diagnosis and therapy of aggressive sarcomas.   

Speaker's short biography :

Eda Machado completed her doctorate degree in Biochemistry/Biology from Nova University of Lisbon (UNL) – ITQB. During her graduate studies in the laboratory of Dr. Júlia Costa, she focused on the understanding of the post-translational process of glycosylation with specific attention to the synthesis of tumor associated cancer antigens. This sparked her interest to continue her path in investigating the molecular and cellular mechanisms at the basis of cancer progression. In the laboratory of Dr. Alessandra d’Azzo at St. Jude Children’s Research Hospital, Memphis, TN, her post-doctoral years have been dedicated to understand lysosomal regulation and processing of substrates, with specific emphasis to lysosomal function in cancer progression. In a renowned laboratory for studying severe congenital and rare lysosomal storage disorders (LSDs) such as sialidosis caused by deficiency of the lysosomal neuraminidase 1 (NEU1), Dr. Machado focused her attention on the role of NEU1 in regulating the physiological process of lysosomal exocytosis found to be hijacked by cancer cells to transition to an aggressive, invasive and drug resistant state. Lately, she has been interested in further exploring the impact of this cellular mechanism in contributing to the heterogeneous cancer mass and to the interplay between cancer cells and their environment during invasion, migration and metastasis, ultimately aiming for the development of new therapies.