Organelle morphology and positioning orchestrate physiological and disease-associated processes.

In cells, organelles are distributed nonrandomly to regulate cells' physiological and disease-associated processes. Based on their morphology, position within the cell, and contacts with other organelles, they exert different biological functions. Endo-lysosomes are critical cell metabolism and nutrient-sensing regulators modulating cell growth and cellular adaptation in response to nutrient availability. Their spatial distribution is intimately linked to their function. In this review, we will discuss the role of endolysosomes under physiological conditions and in the context of cancer progression, with a special focus on their morphology, the molecular mechanisms determining their subcellular position, and the contacts they form with other organelles. We aim to highlight the relationship between cell architecture and cell function and its impact on maintaining organismal homeostasis.

Blood flow diverts extracellular vesicles from endothelial degradative compartments to promote angiogenesis.

Extracellular vesicles released by tumors (tEVs) disseminate via circulatory networks and promote microenvironmental changes in distant organs favoring metastatic seeding. Despite their abundance in the bloodstream, how hemodynamics affect the function of circulating tEVs remains unsolved. We demonstrated that efficient uptake of tEVs occurs in venous endothelial cells that are subjected to hemodynamics. Low flow regimes observed in veins partially reroute internalized tEVs toward non-acidic and non-degradative Rab14-positive endosomes, at the expense of lysosomes, suggesting that endothelial mechanosensing diverts tEVs from degradation. Subsequently, tEVs promote the expression of pro-angiogenic transcription factors in low flow-stimulated endothelial cells and favor vessel sprouting in zebrafish. Altogether, we demonstrate that low flow regimes potentiate the pro-tumoral function of circulating tEVs by promoting their uptake and rerouting their trafficking. We propose that tEVs contribute to pre-metastatic niche formation by exploiting endothelial mechanosensing in specific vascular regions with permissive hemodynamics.

Circulating extracellular vesicles and tumor cells: sticky partners in metastasis.

The intravascular behavior of tumor-derived extracellular vesicles (EVs) and circulating tumor cells (CTCs) lies at the heart of the metastatic cascade. Their capacity to disseminate and stop at specific vascular regions precedes and determines the formation of metastatic foci. We discuss in detail the central role of cellular adhesion molecules (CAMs) that are present on EV/CTC surface, as well as their endothelial ligands, in dictating their arrest site and their capacity to exit the vasculature. We focus on the differences and similarities between CAMs on CTCs and EVs, and speculate about their role in the organotropism of different cancer types. Better understanding of the binding mechanisms might pinpoint potential targets for novel therapies.