Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis

• Published in: Cell Vol. 158; no. 5; pp. 1110 - 1122
• Main Authors: Aceto, Nicola, Bardia, Aditya, Miyamoto, David T., Donaldson, Maria C., Wittner, Ben S., Spencer, Joel A., Yu, Min, Pely, Adam, Engstrom, Amanda, Zhu, Huili, Brannigan, Brian W., Kapur, Ravi, Stott, Shannon L., Shioda, Toshi, Ramaswamy, Sridhar, Ting, David T., Lin, Charles P., Toner, Mehmet, Haber, Daniel A., Maheswaran, Shyamala
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-08-2014
• Subjects: Animals; Breast Neoplasms - pathology; Breast Neoplasms - physiopathology; Cell Line, Tumor; Disease Models, Animal; Female; gamma Catenin - metabolism; 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
• ISSN: 0092-8674; 1097-4172
• 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.
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•CTC clusters originate as oligoclonal groups of cells from the primary tumor•CTC clusters exhibit increased metastatic propensity compared to single CTCs•Abundance of CTC clusters in patients denotes adverse outcome•Plakoglobin mediates CTC cluster formation, enhancing metastatic spread
Circulating tumor cell (CTC) clusters originating from oligoclonal primary tumor cells exhibit increased metastatic potential compared to single CTCs and indicate adverse outcome in cancer patients.