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1.
bioRxiv ; 2023 Aug 22.
Article in English | MEDLINE | ID: mdl-37645762

ABSTRACT

The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, are able to invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis and here we show that FN stimulates VSMCs to secrete small extracellular vesicles (sEVs) by activating the ß1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. Spatially, sEV were secreted via filopodia-like cellular protrusions at the leading edge of migrating cells. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo. Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI. In vitro assays identified collagen VI as playing the key role in cell adhesion and invasion. Taken together our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collage VI enriched sEVs by VSMCs. These sEVs stimulate migration and invasion by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction forces to enable VSMC movement within the complex vascular ECM network.

2.
Nat Cell Biol ; 22(11): 1371-1381, 2020 11.
Article in English | MEDLINE | ID: mdl-33077910

ABSTRACT

Tumour growth and invasiveness require extracellular matrix (ECM) degradation and are stimulated by the GALA pathway, which induces protein O-glycosylation in the endoplasmic reticulum (ER). ECM degradation requires metalloproteases, but whether other enzymes are required is unclear. Here, we show that GALA induces the glycosylation of the ER-resident calnexin (Cnx) in breast and liver cancer. Glycosylated Cnx and its partner ERp57 are trafficked to invadosomes, which are sites of ECM degradation. We find that disulfide bridges are abundant in connective and liver ECM. Cell surface Cnx-ERp57 complexes reduce these extracellular disulfide bonds and are essential for ECM degradation. In vivo, liver cancer cells but not hepatocytes display cell surface Cnx. Liver tumour growth and lung metastasis of breast and liver cancer cells are inhibited by anti-Cnx antibodies. These findings uncover a moonlighting function of Cnx-ERp57 at the cell surface that is essential for ECM breakdown and tumour development.


Subject(s)
Breast Neoplasms/enzymology , Calnexin/metabolism , Cell Movement , Endoplasmic Reticulum/enzymology , Extracellular Matrix/metabolism , Liver Neoplasms/enzymology , Lung Neoplasms/enzymology , Podosomes/enzymology , Protein Disulfide-Isomerases/metabolism , Animals , Antineoplastic Agents, Immunological/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Calnexin/antagonists & inhibitors , Cell Line, Tumor , Endoplasmic Reticulum/pathology , Extracellular Matrix/pathology , Female , Glycosylation , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Lung Neoplasms/secondary , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , NIH 3T3 Cells , Neoplasm Invasiveness , Podosomes/pathology , Protein Transport , Proteolysis , Xenograft Model Antitumor Assays , alpha-Galactosidase/metabolism
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