SERPINE2 and SLPI drive metastasis by enabling breast cancer cells to form vascular-like networks.
Major finding: SERPINE2 and SLPI drive metastasis by enabling breast cancer cells to form vascular-like networks.
Approach: A mouse model of breast cancer heterogeneity was generated using molecular barcoding.
Impact: Anticoagulant-driven vascular mimicry supports tumor perfusion and enhances intravasation.
Primary tumors are composed of heterogeneous populations with varying metastatic potential. To characterize the specific contributions of distinct clonal populations to tumor growth and metastatic progression, Wagenblast and colleagues generated a mouse model of tumor heterogeneity, in which molecular barcoding was used to label individual transplanted breast cancer cells and their progeny. Analysis of the frequency of barcoded populations revealed that the proportion of clones present in secondary metastatic sites, including the lymph node, lung, liver, brain, and blood, did not correlate with the abundance of these clones in the primary tumor. Individual clones that were less abundant in the primary tumor gave rise to circulating tumor cells (CTC) in the bloodstream and contributed to colonization of secondary sites, whereas a distinct group of clones participated in metastatic spread via the lymphatic system. Overexpression of serpin peptidase inhibitor, clade E member 2 (SERPINE2) and secretory leukocyte peptidase inhibitor (SLPI) was specifically detected in clones capable of entering the vasculature and was associated with metastatic relapse in the lungs of patients with breast cancer. Intriguingly, expression of SERPINE2 and SLPI was both necessary and sufficient to stimulate the formation of vascular-like tubular networks by breast cancer cells via a phenomenon known as vascular mimicry, which facilitates perfusion of primary tumors and correlates with poor clinical outcome. This increase in tumor cell–lined extravascular channels was associated with an increase in CTCs and a subsequent increase in lung metastatic burden. In addition, treatment with the anticoagulant warfarin increased the number of CTCs and lung metastases, suggesting that the anticoagulant function of SERPINE2 and SLPI both maintains blood flow through the extravascular network and promotes intravasation. These results identify SERPINE2- and SLPI-driven vascular mimicry as a critical mechanism underlying increased capacity for metastatic progression.
Wagenblast E, Soto M, Gutiérrez-Ángel S, Hartl CA, Gable AL, Maceli AR, et al. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature 2015;520:358–62.
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