Abstract
Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths. The integrin ITGB3 has been previously described to play an essential role in breast cancer metastasis, but the precise mechanisms remain undefined. We have now uncovered essential and thus far unknown roles of ITGB3 in vesicle uptake. The functional requirement for ITGB3 derives from its interactions with heparan sulfate proteoglycans (HSPGs) and the process of integrin endocytosis, allowing the capture of extracellular vesicles and their endocytosis-mediated internalization. Key for the function of ITGB3 is the interaction and activation of focal adhesion kinase (FAK), which is required for endocytosis of these vesicles. Thus, ITGB3 has a central role in intracellular communication via extracellular vesicles, proposed to be critical for cancer metastasis.
Highlights
Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths
We previously demonstrated that integrin beta 3 (ITGB3) is required for lung metastasis formation[26], but follow-up experiments revealed no defect in the initial homing of shITGB3 cells to the lung (Supplementary Fig. 1a–c)
Building on the findings[26,27,56] that ITGB3 is required for lung metastasis in MDA.MB.[231] cells, we have demonstrated that the underlying mechanism may relate to the role ITGB3 plays in Extracellular vesicles (EVs) uptake and exosome biogenesis
Summary
Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths. EVs are a heterogeneous group of secreted membranous vesicles including microvesicles, ectosomes, and exosomes[6] They have become valuable biomarkers in liquid biopsies, and existing research has focused on their characterization in different cancer types[7,8]. Once released from the donor cell, EVs induce cell signalling, either by interacting with target cell–surface proteins or being taken up into the receiving cell[6,9]. This uptake is currently the least understood step in vesicle-based intercellular communication, and proposed mechanisms range from passive membrane fusion to active uptake via macropinocytosis or endocytosis[12]
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