A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis

Wagenblast, E., Soto, M., Gutierrez-Angel, S., Hartl, C. A., Gable, A. L., Maceli, A. R., Erard, N., Williams, A. M., Kim, S. Y., Dickopf, S., Harrell, J. C., Smith, A. D., Perou, C. M., Wilkinson, J. E., Hannon, G. J., Knott, S. R. (April 2015) A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature, 520 (7547). pp. 358-362. ISSN 0028-0836

URL: http://www.ncbi.nlm.nih.gov/pubmed/25855289
DOI: 10.1038/nature14403


Cancer metastasis requires that primary tumour cells evolve the capacity to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites. Others have demonstrated that individual cells within complex populations show heterogeneity in their capacity to form secondary lesions. Here we develop a polyclonal mouse model of breast tumour heterogeneity, and show that distinct clones within a mixed population display specialization, for example, dominating the primary tumour, contributing to metastatic populations, or showing tropism for entering the lymphatic or vasculature systems. We correlate these stable properties to distinct gene expression profiles. Those clones that efficiently enter the vasculature express two secreted proteins, Serpine2 and Slpi, which were necessary and sufficient to program these cells for vascular mimicry. Our data indicate that these proteins not only drive the formation of extravascular networks but also ensure their perfusion by acting as anticoagulants. We propose that vascular mimicry drives the ability of some breast tumour cells to contribute to distant metastases while simultaneously satisfying a critical need of the primary tumour to be fed by the vasculature. Enforced expression of SERPINE2 and SLPI in human breast cancer cell lines also programmed them for vascular mimicry, and SERPINE2 and SLPI were overexpressed preferentially in human patients that had lung-metastatic relapse. Thus, these two secreted proteins, and the phenotype they promote, may be broadly relevant as drivers of metastatic progression in human cancer.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > breast cancer
diseases & disorders > cancer > metastasis
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
CSHL labs > Hannon lab
School of Biological Sciences > Publications
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: Matt Covey
Date: 8 April 2015
Date Deposited: 14 Apr 2015 20:32
Last Modified: 16 Jul 2021 13:48
PMCID: PMC4634366
Related URLs:
URI: https://repository.cshl.edu/id/eprint/31331

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