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The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis

Abstract

Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial–mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.

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Figure 1: DDR2 stabilizes the cellular SNAIL1 level, post-transcriptionally.
Figure 2: Collagen-I-induced stabilization of SNAIL1 requires DDR2.
Figure 3: DDR2 influences breast cancer cell migration in vitro and metastases in vivo.
Figure 4: Collagen fibre alignment at tumour/ECM boundary.
Figure 5: DDR2 stabilizes SNAIL1 through ERK2 phosphorylation of SNAIL1.
Figure 6: ERK2 phosphorylation of SNAIL1 results in nuclear accumulation and diminished ubiquitylation.
Figure 7: Delineation of the intracellular signalling pathway whereby DDR2 leads to SNAIL1 stabilization and tumour cell invasion/migration.
Figure 8: DDR2 expression is present in most human invasive (Inv.) ductal breast cancers and correlates with the presence of nuclear SNAIL1 and loss of E-cadherin expression.

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Acknowledgements

This work was supported by NIH grant P50CA94056 to the Imaging Core of the Siteman Cancer Center at Washington University, and NIH grants GM080673 and CA143868, and Susan G. Komen for the Cure KG110889 to G.D.L. C.A.C. was supported by NIH grant F31CA165729.

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K.Z., C.A.C., S.M.P. and J.L.P. were involved in project planning, experimental work and data analysis. D.P-W., K.W.E., P.J.K. and G.D.L. were involved in project planning and data analysis. G.D.L. wrote the manuscript. D.P-W. and P.J.K. provided editorial assistance in the writing of the manuscript.

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Correspondence to Gregory D. Longmore.

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Zhang, K., Corsa, C., Ponik, S. et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat Cell Biol 15, 677–687 (2013). https://doi.org/10.1038/ncb2743

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