title: The perivascular niche regulates breast tumour dormancy.
abstract: In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. cmghajar@lbl.gov
authors.forename: Cyrus M
authors.initials: CM
authors.lastname: Ghajar
authors.forename: Héctor
authors.initials: H
authors.lastname: Peinado
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Mori
authors.forename: Irina R
authors.initials: IR
authors.lastname: Matei
authors.forename: Kimberley J
authors.initials: KJ
authors.lastname: Evason
authors.forename: Hélène
authors.initials: H
authors.lastname: Brazier
authors.forename: Dena
authors.initials: D
authors.lastname: Almeida
authors.forename: Antonius
authors.initials: A
authors.lastname: Koller
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hajjar
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
mesh_terms: D000818:Animals; D019046:Bone Marrow Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D018365:Neoplasm, Residual / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000378:metabolism / Q000473:pathology*; D055153:Stem Cell Niche / Q000502:physiology; D019700:Thrombospondin 1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; C082838:Postn protein, mouse; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta