Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / pathology*
  • Breast Neoplasms / physiopathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis / pathology*
  • Neoplastic Cells, Circulating / pathology*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / physiopathology
  • Sequence Analysis, RNA
  • Single-Cell Analysis
  • gamma Catenin / metabolism


  • gamma Catenin

Associated data

  • GEO/GSE51827