Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Nov;22(11):1371-1381.
doi: 10.1038/s41556-020-00590-w. Epub 2020 Oct 19.

ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells

Manon Ros  1   2 , Anh Tuan Nguyen  1 , Joanne Chia  1 , Son Le Tran  1 , Xavier Le Guezennec  1 , Ruth McDowall  1   3 , Sergey Vakhrushev  4 , Henrik Clausen  4 , Martin James Humphries  3 , Frederic Saltel  2 , Frederic André Bard  5   6
Affiliations

ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells

Manon Ros et al. Nat Cell Biol. 2020 Nov.

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.

PubMed Disclaimer

References

    1. Nissen, R., Cardinale, G. J. & Udenfriend, S. Increased turnover of arterial collagen in hypertensive rats. Proc. Natl Acad. Sci. USA 75, 451–453 (1978).
    1. Jabłońska-Trypuć, A., Matejczyk, M. & Rosochacki, S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J. Enzyme Inhib. Med. Chem. 31, 177–183 (2016).
    1. Hotary, K., Allen, E., Punturieri, A., Yana, I. & Weiss, S. J. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J. Cell Biol. 149, 1309–1323 (2000).
    1. Hotary, K. B. et al. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114, 33–45 (2003).
    1. Nguyen, A. T. et al. Organelle specific O-glycosylation drives MMP14 activation, tumor growth, and metastasis. Cancer Cell 32, 639–653.e6 (2017).

Publication types

MeSH terms

LinkOut - more resources