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

Nature Cell Biology volume 22, pages 1371–1381 (2020)Cite this article

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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.

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Fig. 1: GALA induces Cnx glycosylation and expression in invadosomes.
Fig. 2: Cnx and ERp57 are required for ECM degradation.
Fig. 3: Glycosylated Cnx is required for ECM degradation.
Fig. 4: Cnx and ERp57 are required for ECM disulfide bond reduction.
Fig. 5: Anti-Cnx antibody treatment prevents tumour metastasis.
Fig. 6: Antibody-mediated inhibition of Cnx reduces tumour growth.

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Data availability

All data supporting the findings of this study are available from the corresponding author upon reasonable request. The mass spectrometry data are available via ProteomeXchange with the identifier PXD021202. Source data are provided with this paper.

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Acknowledgements

We thank D. Fass and M. Molinari for insightful discussions about disulfide bonds, Cnx and ERp57, and G. Van der Goot for plasmids and advice. We also thank the Advanced Molecular Pathology Laboratory at the IMCB for mouse histology services and the Bordeaux Imaging Center (BIC) for their support in this study. This work was supported by A*STAR, Cancer Research UK (grant C13329/A21671 to M.J.H.), La Fondation pour la Recherche Médicale (grant number DEQ20180839586) and Integrated Cancer Research (SIRIC, BRIO).

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Authors and Affiliations

  1. Institute of Molecular and Cell Biology, A*STAR, Proteos, Singapore

    Manon Ros, Anh Tuan Nguyen, Joanne Chia, Son Le Tran, Xavier Le Guezennec, Ruth McDowall & Frederic André Bard

  2. Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000 Bordeaux, France, Bordeaux, France

    Manon Ros & Frederic Saltel

  3. Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

    Ruth McDowall & Martin James Humphries

  4. Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Sergey Vakhrushev & Henrik Clausen

  5. Department of Biochemistry, National University of Singapore, Singapore, Singapore

    Frederic André Bard

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Contributions

M.R. designed and performed experiments. J.C., S.V. and H.C. contributed to the analyses of Cnx glycosylation and glycosylation sites. A.T.N. performed most of the mouse experiments, and S.L.T. and X.L.G. performed the ECM characterization and degradation experiments. R.M. and M.J.H. participated in the initial characterization of the function of Cnx glycosylation. M.J.H. contributed to the manuscript and mentoring of R.M., and F.S. contributed to discussion, experimental design and mentoring of M.R. F.A.B. designed experiments and wrote the manuscript.

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Correspondence to Frederic André Bard.

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Extended data

Extended Data Fig. 1 Cnx glycosylation and translocation.

a, Immunoblot analysis of the level of Tn-modified Cnx in human liver tumours (T) versus the corresponding normal liver tissues (NT) from 20 liver cancer patients. b, Quantification of calnexin staining colocalizing with cortactin staining in NIH3T3vSrc cells. c, Immunofluorescence of MDA ER-G2 cells stained with calnexin and cortactin. Scale bar, 20μm. Source data and unmodified blots of Extended Data Fig. 1 can be found in files named Source Data Extended Data Fig. 1.

Source data

Extended Data Fig. 2 Cnx and ERp57 are essential for ECM degradation.

a, Schematic of matrix degradation assay. b, Relative intensity of degraded collagen antibody staining after incubation with NIH 3T3vSrc control cells and NIH 3T3vSrc Cnx KD cells. Values indicate the mean ± SEM for 3 replicates and were analyzed using a two-tailed Student’s t-test. Representatives images can be found on the right. Scale bar, 20 μm. siRNA efficacy and its quantification can be found below. c, Workflow on ImageJ software to quantify degradation per nuclei. d, Quantification of ECM degradation assay of NIH3T3vSrc cells incubated with control antibody (IgG control) or 2 different anti-Cnx antibodies. Values indicate the mean ± SEM of normalized fold change for 3 replicates and were analyzed using a two-tailed Student’s t-test. e, Western blot analysis and quantification of cnx siRNA associated to Fig. 2d. Values were analyzed using a two-tailed Student’s t-test. f, Quantification of ECM degradation assay of NIH3T3vSrc cells transfected with control siRNA (siNT5) or siRNA against Cnx (siCnx). Values indicate the mean ± SEM of normalized fold changes for 3 replicates and were analyzed using a two-tailed Student’s t-test. Western blot and quantification of siRNA efficacy can be found on the right. g, Immunoblot analysis of MMPs protein level in NIH3T3vSrc transfected with control siRNA (siNT5) or siRNA against Cnx (siCnx). siRNA efficacy can be found on the right (this quantification is for Fig S2G, S2H and S2I, the experiments were done with the same samples). Values indicate the mean ± SEM of 3 replicates and were analyzed using a two-tailed Student’s t-test. h, Quantification of MMP activity by FRET assay of MDA ER-G2 cells transfected with control siRNA (siNT5) or siRNA against cnx (siCnx). Quantification of siRNA efficacy can be found on Supp Fig. 2g. i, Immunofluorescence of NIH3T3vSrc cells transfected with control siRNA (siNT5) or siRNA against Cnx (siCnx) and stained with MMP14 and the invadosome marker cortactin. Scale bar, 5 μm. Quantification of siRNA efficacy can be found on Supp Fig. 2g. j, Western blot and quantification of siRNA in Fig. 2h. Values indicate the mean ± SEM of 3 replicates and were analyzed using a two-tailed Student’s t-test. Source data and unmodified blots of Extended Data Fig. 2 can be found in files named Source Data Extended Data 2.

Source data

Extended Data Fig. 3 Disulfide bonds are abundant in liver ECM and reduced by Cnx/ERp57.

a, Immunofluorescence of collagens I and III and OX133 on decellularized liver, untreated or treated with TCEP and NEM. Scale bar, 50 μm. b, Immunofluorescence of collagen I and fibronectin on decellularized liver, untreated or treated with TCEP and NEM. Scale bar, 50 μm. c, Immunofluorescence of rat tail ECM, treated or non-treated with TCEP and NEM and stained with OX133 antibody. Scale bar, 20 μm. d, Western blot and quantification of siRNA efficacy associated to Fig. 4d. Values represent the mean ± SEM of 2 replicates. e, Immunofluorescence of collagen incubated with NIH3T3vSrc (not shown), with or without NEM, and stained with ERp57 antibody. Collagen was previously coupled to 5-carboxy-X-rhodamin succinimidyl ester before cell seeding. Scale bar, 10 μm. f, Quantification of ECM degradation assay of NIH3T3vSrc cells incubated with GSH (+GSH) or with GPx and H2O2 (+GPx). Values indicate the mean ± SEM of normalized fold changes for 3 and replicates respectively and were analyzed using a two-tailed Student’s t-test. g, Western blot and quantification of siRNA efficacy associated to Fig. 4f. Values represent the mean ± SEM of 3 replicates and were analyzed using a two-tailed Student’s t-test. h, Quantification of ECM degradation assay of MDA ER-G2 transfected with control siRNA or 2 different ERp57 siRNA (siERp57 #1 and #2). Collagen disulfide bonds were chemically reduced using TCEP (+TCEP) or left untreated (- TCEP) before cell seeding. Values indicate the mean ± SEM of normalized fold changes for 3 replicates and were analyzed using a two-tailed Student’s t-test. Western blot and quantification of siRNA efficacy can be found on the right. Source data and unmodified blots of Extended Data Fig. 3 can be found in files named Source Data Extended Data Fig. 3.

Source data

Extended Data Fig. 4 Cnx is essential for tumour growth.

a, Schematic diagram of experiments using a mouse model of breast cancer metastasis to the lung to test anti-calnexin antibody. b, Schematic diagram of the workflow of the calnexin antibody treatment in a mouse model for liver cancer and its lung metastasis.

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Supplementary Table 1

Table containing patient data.

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Ros, M., Nguyen, A.T., Chia, J. et al. ER-resident oxidoreductases are glycosylated and trafficked to the cell surface to promote matrix degradation by tumour cells. Nat Cell Biol 22, 1371–1381 (2020). https://doi.org/10.1038/s41556-020-00590-w

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