title: Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.
abstract: Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
authors.forename: Trevor T
authors.initials: TT
authors.lastname: Price
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Monika L
authors.initials: ML
authors.lastname: Burness
authors.affiliation: Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Sivan
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Warner
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
authors.forename: Renee
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
authors.forename: Clara H
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Olivere
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27707, USA.
authors.forename: Karrie
authors.initials: K
authors.lastname: Comatas
authors.affiliation: GlycoMimetics Inc., Rockville, MD 20850, USA.
authors.forename: John
authors.initials: J
authors.lastname: Magnani
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27707, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kim Lyerly
authors.affiliation: Department of Surgery, Duke University, Durham, NC 27707, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Pathology, Duke University, Durham, NC 27707, USA.
authors.forename: Chad M
authors.initials: CM
authors.lastname: McCall
authors.affiliation: Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, NC 27707, USA. dorothy.sipkins@dm.duke.edu.
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Sipkins
mesh_terms: D000818:Animals; D001596:Benzylamines; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000150:complications* / Q000378:metabolism*; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000080027:Cyclams; D019040:E-Selectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D061206:Neoplasm Micrometastasis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D019040:E-Selectin; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor