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Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer

Oncogene volume 41, pages 5176–5185 (2022)Cite this article

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Abstract

Tissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and poor survival. The role of TF signaling on the early phases of metastasis has never been addressed. Here, we show an association between TF expression and metastasis as well as cancer stemness in 574 breast cancer patients. In preclinical models, blockade of TF signaling inhibited metastasis tenfold independent of primary tumor growth. TF blockade caused a reduction in epithelial-to-mesenchymal-transition, cancer stemness and expression of the pro-metastatic markers Slug and SOX9 in several breast cancer cell lines and in ex vivo cultured tumor cells. Mechanistically, TF forms a complex with β1-integrin leading to inactivation of β1-integrin. Inhibition of TF signaling induces a shift in TF-binding from α3β1-integrin to α6β4 and dictates FAK recruitment, leading to reduced epithelial-to-mesenchymal-transition and tumor cell differentiation. In conclusion, TF signaling inhibition leads to reduced pro-metastatic transcriptional programs, and a subsequent integrin β1 and β4-dependent reduction in metastasic dissemination.

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Fig. 1: TF associates with metastasis in patients with ER-negative breast tumors, and TF signaling induces metastasis.
Fig. 2: TF signaling inhibition reduces EMT and CSC program in vitro.
Fig. 3: Blockade of TF signaling reduces EMT and CSC program in ex vivo cells.
Fig. 4: TF determines β1-integrin localization in the cell membrane.
Fig. 5: Inhibition of TF signaling increases expression of, and crosstalk with α6β4-integrin.
Fig. 6: Schematic overview.

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Acknowledgements

We would like to thank Y.W. van den Berg for immunohistochemical staining and E.H. Laghmani for technical assistance.

Funding

This study was supported by the Dutch Cancer Society (UL 2015-7594), The Netherlands Organization for Scientific Research (VIDI 91710329) and Worldwide Cancer Research (15-1186). VYB and CSL are partially supported by the NIH/NCI (grant R01CA190717).

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Authors and Affiliations

  1. Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

    Betül Ünlü, Begüm Kocatürk, Araci M. R. Rondon, Nathalie Swier, Rob F. P. van den Akker & Henri H. Versteeg

  2. Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine University of Cincinnati, Cincinnati, OH, USA

    Clayton S. Lewis & Vladimir Y. Bogdanov

  3. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands

    Danielle Krijgsman, Iris Noordhoek, Erik J. Blok & Peter J. K. Kuppen

  4. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA

    Wolfram Ruf

  5. Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Germany

    Wolfram Ruf

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  1. Betül Ünlü
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Contributions

BÜ, BK, AMdRR, CSL, NS, and RFPvdA performed the experiments, acquired and analyzed data; EJB, IN and DK performed immunohistochemical stainings and analyzed data. PJKK, VYB and WR provided study material and reagents. BÜ and HHV designed the project, wrote the paper and prepared the figures. All authors reviewed and approved the paper.

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Correspondence to Henri H. Versteeg.

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Ünlü, B., Kocatürk, B., Rondon, A.M.R. et al. Integrin regulation by tissue factor promotes cancer stemness and metastatic dissemination in breast cancer. Oncogene 41, 5176–5185 (2022). https://doi.org/10.1038/s41388-022-02511-7

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