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

Different clones of a mammary tumour cell line possess differential abilities to contribute to the formation of metastasis; the expression of Serpine2 and Slp1 proteins drives vascular mimicry and metastasis to the lung, with similar associations observed in human data sets, and these proteins also function as anticoagulants, thus further promoting extravasation of tumour cells. Using a mouse model of tumour heterogeneity that can be perturbed genetically to validate drivers of specific clonal behaviours, Elvin Wagenblast et al. demonstrate that different clones of a mammary tumour cell lines possess different abilities to contribute to the formation of metastasis. The expression of Serpine2 and Slpi proteins correlates with lung metastasis, and similar associations were observed in human datasets. Serpine2 and Slpi act as anticoagulants and also allow tumour cells to undergo vascular mimicry, whereby the tumour cells themselves form part of blood vessels and contribute to increased intravasation by building more leaky blood vessels. Cancer metastasis requires that primary tumour cells evolve the capacity to intravasate into the lymphatic system or vasculature, and extravasate into and colonize secondary sites1. Others have demonstrated that individual cells within complex populations show heterogeneity in their capacity to form secondary lesions2,3,4,5. 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.