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.