Cancer cells transfer invasive properties through collagen-tracks

Abstract Invasion and migration through the extracellular matrix are prerequisites for metastasis, the leading cause of cancer-related deaths. During tumor development, the extracellular matrix is remodeled, including by overexpressing type I collagen that facilitate cancer dissemination. Most studies have focused on events at the leading edge as cells invade. We describe a new event at the trailing edge, as cells detach from the matrix. We show that small vesicles containing the collagen receptor DDR1 are left behind on collagen fibrils in the migration path. We named these structures attached to the collagen fibers "collagen-tracks". The vesicles are similar in size to exosomes but lack the exosome markers, and they also are different to migrasomes. We show that collagen-track formation is stimulated by DDR1 and by factors that promote adhesion, including collagen cross-linking. We report the protein, mRNA and miRNA content of collagen-tracks. They contain adhesion proteins, suggesting that they form when membrane fragments containing adhesions are torn from the cell as it migrates along collagen fibrils. We show that collagen-tracks are deposited by breast cancer cells in 3D matrices in vitro and in vivo. Collagen-tracks are stable and can be taken up by surrounding cells, promoting epithelial to mesenchymal transition, matrix degradation and invasion, finally leading to increased lung metastasis of breast cancer cells. In summary, we have identified and characterized a new vesicle entity directly attached to collagen fibrils that plays a role in cell-cell communication and can transfer invasive properties to surrounding cells. We conclude that cancer-related collagen-tracks are a new player acting locally to drive tumor invasion and metastasis