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Mechanisms of leading edge protrusion in interstitial migration

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On two-dimensional substrates, cells protrude by assembling a thin actin-rich veil at their leading edge. The molecular and biophysical mechanisms underlying formation of these protrusions are now well understood. However, in physiology and pathophysiology, cells migrate primarily in more complex three-dimensional environments: leukocytes migrate through a wide variety of tissues to combat inflammation and cancer cells leave the primary tumour to metastasise. Despite relevance to immunity, development, and cancer, our understanding of the actin structures driving protrusion in three-dimensional environments is poor. We studied chemotaxis of HL60 neutrophil-like cells through microfluidic channels with 5μmx5μm cross-sections. In these interstices, the leading edge of migrating cells consisted of an actin-rich slab several microns thick filling the whole channel cross-section and composed of two distinct F-actin networks: an adherent network that polymerised perpendicular to cell-wall interfaces and a free network that grew from the free membrane at the cell front. Photobleaching experiments revealed that both networks interacted mechanically. Polymerisation of the free network was dependent upon the arp2/3 complex but formation of the adherent network was not, suggesting that each network resulted from polymerisation by distinct nucleators. Removal of the free network by arp2/3 inhibition led to a switch in mode of protrusion with the formation of blebs at the leading edge but did not inhibit migration. Together these data suggest a picture of cell migration in interstices where medial growth of the adherent network prevents retrograde movement of the free network enabling new polymerisation to be converted into forward protrusion.

This talk is part of the BSS Formal Seminars series.

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