Cancer cells are exposed to major compressive and shearing forces during invasion and metastasis, leading to extensive plasma membrane damage. To survive this mechanical stress, they need to repair membrane injury efficiently. Targeting the membrane repair machinery is thus potentially a new way to prevent invasion and metastasis. We show here that annexin-A2 (ANXA2) is required for membrane repair in MDA-MB-231 cells, a highly invasive triple-negative breast cancer cell line. Mechanistically, we show by fluorescence and electron microscopy that cells fail to reseal membrane damaged by shear stress when ANXA2 is silenced or the protein is inhibited with neutralizing antibody. Silencing of ANXA2 has no effect on proliferation in vitro, and even accelerates migration in wound healing assays, but reduces tumor cell dissemination in both mice and zebrafish. We show that high expression of ANXA2 predicts poor prognosis in high-grade lung, ovarian, gastric and breast cancers. We expect that inhibiting membrane repair will be particularly effective in these aggressive, poor prognosis tumors because they rely on the membrane repair machinery to survive membrane damage during tumor invasion and metastasis. This could be achieved either with monoclonal anti-ANXA2 antibodies, which have been shown to inhibit metastasis of MDA-MB-231 cells, or with small molecule drugs.
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
Metastasis is the leading cause of cancer-related deaths. During this process, tumor cells acquire invasive and migratory capacities in order to invade the surrounding tissues. To achieve this, the tumor microenvironment including the extracellular matrix (ECM) is altered to facilitate cancer cell proliferation and dissemination. Extracellular vesicles (EVs), such as exosomes or migrasomes, are already known to induce pro-tumor features such as migration, promoting tumor development and metastasis formation. Here we highlight a new type of EVs, referred as tracks, released by cancer cells during migration and specifically attached along collagen fibers. These tracks, identified by discoidin receptor 1 (DDR1) enrichment, are promoted when cell-ECM interactions are increased, such as in tumors. We characterized these tracks, their ultrastructure as well as their molecular composition in terms of proteins and nucleic acids, showing that they are different from classical EVs known so far. Moreover, these tracks are very stable structures and can be internalized by surrounding cells. After internalization, they modify the differentiation status and the phenotype of recipient cells, promoting epithelial to mesenchymal transition, matrix degradation and invasion. Thus, we identified a new class of collagen-associated EVs, tracks, that play a role in cell-cell communication by transferring invasive properties. Consequently, these cancer-related tracks could be a new player in the tumor invasion process.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.