Exosomes (red) localize to the tips of filopodia (spiky structures at front of cell, green) and are left in trails behind migrating cells. Image credit: McAtee et al. (CC BY 4.0)
Cell migration is a crucial process that underpins both healthy functions – such as organ and blood vessel development, and the formation of synaptic connections between neurons – and pathological events like cancer metastasis. For cells to migrate, they must reorganize their cytoskeleton to form specialized structures that support their movement.
This reorganization includes filopodia, which are slender protrusions that play key roles in sensing directional cues at the leading edge of migrating cells and initiating contact with other cells. The extracellular signals that trigger the formation of filopodia remain poorly understood, but recent research suggests that extracellular vesicles may be involved in this process.
Also known as exosomes, these vesicles are membrane-enclosed particles that carry proteins, lipids, and nucleic acids between cells, representing an alternative mode of cellular communication. McAtee et al. aimed to determine whether exosomes could also promote filopodia formation.
They studied two distinct systems: cancer cells, where filopodia facilitate metastasis, and rat neurons, where they promote synapse formation. In both contexts, exosomes emerged as potent, general regulators of filopodia formation, indicating a broad role in controlling this fundamental cellular behavior.
Using genetic inhibition of exosome secretion, combined with add-back of extracellular vesicles, McAtee et al. demonstrated a direct causal relationship between exosomes and filopodia formation. In neurons, filopodia matured into dendritic spines – critical structures for synaptic connectivity between neurons. A quantitative analysis of neurons confirmed that exosomes indeed promoted the formation of dendritic spines and synapses. They also identified the exosomal protein THSD7A as key in driving filopodia formation in both neurons and cancer cells. Moreover, in cancer cells, the secretion of THSD7A-containing exosomes, filopodia formation, cell migration, and metastatic colony formation were regulated by a growth factor receptor known as endoglin.
The study by McAtee et al. highlights a novel role for extracellular vesicles in filopodia formation, enhancing our understanding of how cells migrate in health and disease. Interestingly, both molecules identified as cargoes of filopodia-regulating exosomes are associated with disease: endoglin with hereditary hemorrhagic telangiectasia, and THSD7A with a kidney disease called secondary membranous nephropathy. This suggests that dysregulation of filopodia may occur in these conditions. Furthermore, endoglin and/or THSD7A could serve as potential targets for anti-cancer therapies. Indeed, some promising investigations have already employed anti-endoglin antibodies to inhibit metastasis.
