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Cell. 2014 Aug 28;158(5):1110-1122. doi: 10.1016/j.cell.2014.07.013.

Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis.

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA 02129, USA.
2
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.
3
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.
4
Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA.
5
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.
6
Center for Bioengineering in Medicine, Harvard Medical School, Boston, MA 02129, USA; Department of Surgery, Harvard Medical School, Boston, MA 02129, USA.
7
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.
8
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.

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.

PMID:
25171411
PMCID:
PMC4149753
DOI:
10.1016/j.cell.2014.07.013
[Indexed for MEDLINE]
Free PMC Article
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