title: A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis.
abstract: 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.
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Elvin
authors: E
authors: Wagenblast
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Mar
authors: M
authors: Soto
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Sara
authors: S
authors: Gutiérrez-Ángel
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Christina A
authors: CA
authors: Hartl
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Annika L
authors: AL
authors: Gable
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Ashley R
authors: AR
authors: Maceli
authors: 1] Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robininson Way, Cambridge CB2 0RE, UK.
authors: Nicolas
authors: N
authors: Erard
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Alissa M
authors: AM
authors: Williams
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Sun Y
authors: SY
authors: Kim
authors: Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
authors: Steffen
authors: S
authors: Dickopf
authors: Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors: J Chuck
authors: JC
authors: Harrell
authors: Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.
authors: Andrew D
authors: AD
authors: Smith
authors: Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors: Charles M
authors: CM
authors: Perou
authors: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
authors: John E
authors: JE
authors: Wilkinson
authors: 1] Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robininson Way, Cambridge CB2 0RE, UK.
authors: Gregory J
authors: GJ
authors: Hannon
authors: 1] Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robininson Way, Cambridge CB2 0RE, UK.
authors: Simon R V
authors: SR
authors: Knott
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000378:metabolism; D001943:Breast Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D012008:Recurrence; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000378:metabolism; D017422:Sequence Analysis, DNA; D058258:Serpin E2 / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D053481:Secretory Leukocyte Peptidase Inhibitor; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C506815:Slpi protein, mouse