Morparthi, S. B. | bioRxiv Science

bioRxiv2026

Hck signaling drives long-distance ECM degradation through endo-exocytosis coupling in macrophages.

The diversity of strategies implicated in extracellular matrix (ECM) degradation supporting cell invasion has been poorly achieved. Unlike invasive breast cancer cells, which predominantly degrade the ECM locally via an invadosome-associated degradation, dynamic quantification of live imaging of degradation of physiological ECM such as fibrinogen showed that macrophages employ different modes of ECM degradation since digesting ECM both locally and at long distance. Long distance degradation occurring in macrophage is dependent on both matrix metalloproteases (MMPs) and cathepsins release. Optogenetic manipulation showed that HCK signaling specifically regulates positively this new mode of fibrinogen degradation by increasing cathepsins release and activating localized fusion of acidic CD63-endolysosome vesicles at the vicinity of clathrin hotspots at the rear of macrophages, appearing as a new exo-endocytosis coupling. Computational biology and in silico simulations support the importance of the fine spatiotemporal coordination between MMPs and cathepsin activities, and regulation of cathepsin activity by local acid release. Different mode of ECM degradation can thus coexist and this highlight the importance of understanding the cathepsins-MMPs synergy in shaping invasive behavior across different physio-pathological invasion processes.

cell biology↗

bioRxiv2026

Vimentin bridges scales to convert polarized cell locomotion into coordinated collective migration

Collective cell migration is central in development and disease. Vimentin is an intermediate filament protein expressed by epithelial cells at the edge of wounds where collective cell migration is most efficient. Yet, its functional role in this context remains underexplored. Here, we show that vimentin, over-expressed in cells undergoing partial epithelial to mesenchymal transition at the edge of epithelial monolayers, has a multiscale impact on the whole monolayer mechano-dynamics. Vimentin knock-down delays wound closure, reduces cell coordination, while increasing traction forces exerted by cells on the substratum. It also disrupts the directionality of leader cells migration, as well as the cohesion and coordinated motion of cells deep in the monolayer. We further show that vimentin promotes the conversion of polarized cell locomotion into coordinate collective migration by polarizing actin, focal adhesions and traction forces, sustaining leader cells lamellipodium protrusive activity and directionality, while allowing mechanical coupling of leader with follower cells. Altogether, we show that vimentin is essential for bridging polarized single cell locomotion and coordinated collective migration to allow efficient collective migration. Significant statementEpithelial cells migrate coordinately to repair tissue. Vimentin, transiently enriched at the wound edge plays a key role in guiding this process by converting polarized cell locomotion into coordinate collective migration, enabling leader cells to polarize, form stable protrusions, and maintain directed migration, while allowing mechanical coupling of front cells with followers, necessary for efficient coordinated collective migration. These findings reveal vimentin, a known EMT marker, as a novel positive regulator of efficient wound healing.

cell biology↗