title: Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis.
abstract: Circulating tumor cell clusters (CTC clusters) are present in the blood of patients with cancer but their contribution to metastasis is not well defined. Using mouse models with tagged mammary tumors, we demonstrate that CTC clusters arise from oligoclonal tumor cell groupings and not from intravascular aggregation events. Although rare in the circulation compared with single CTCs, CTC clusters have 23- to 50-fold increased metastatic potential. In patients with breast cancer, single-cell resolution RNA sequencing of CTC clusters and single CTCs, matched within individual blood samples, identifies the cell junction component plakoglobin as highly differentially expressed. In mouse models, knockdown of plakoglobin abrogates CTC cluster formation and suppresses lung metastases. In breast cancer patients, both abundance of CTC clusters and high tumor plakoglobin levels denote adverse outcomes. Thus, CTC clusters are derived from multicellular groupings of primary tumor cells held together through plakoglobin-dependent intercellular adhesion, and though rare, they greatly contribute to the metastatic spread of cancer.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Aceto
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Aditya
authors.initials: A
authors.lastname: Bardia
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Miyamoto
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Donaldson
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.affiliation: Advanced Microscopy Program, Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Spencer
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Advanced Microscopy Program, Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Pely
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Engstrom
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Huili
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Brannigan
authors.affiliation: Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA; Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Stott
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Toshi
authors.initials: T
authors.lastname: Shioda
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Ting
authors.affiliation: Advanced Microscopy Program, Wellman Center for Photomedicine and Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, 1350 Massachusetts Avenue, Cambridge, MA 02138, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.affiliation: Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA; Department of Surgery, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Toner
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: dhaber@mgh.harvard.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Surgery, Harvard Medical School, Boston, MA 02129, USA. Electronic address: maheswaran@helix.mgh.harvard.edu.
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology*; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D051185:gamma Catenin / Q000378:metabolism
chemical_list: D051185:gamma Catenin