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

Menée à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome hépatocellulaire et menée à l'aide de modèles murins de cancer du foie ou de cancer du sein avec métastases pulmonaires, cette étude démontre que la calnexine du réticulum endoplasmique des cellules cancéreuses est glycosylée et acheminée vers la surface pour favoriser la dégradation de la matrice extracellulaire

Résumé en anglais

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.