Circulating Tumor Cell Clusters are Oligoclonal Precursors of Breast Cancer Metastasis

By N. Aceto, A. Bardia, D. Miyamoto, M. C. Donaldson, Ben S. Wittner, J. Spencer, Min Yu, Adam Pely, Amanda Engstrom, Huili Zhu and 10 more. Cell, 2014

2,243 citations recorded by the source corpus.

SUMMARY Clusters of circulating tumor cells (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 23-50-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 while rare, they greatly contribute to the metastatic spread of cancer.

Subfields: Cancer Research, Cell Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/d9bbd8ad754ab417db569b856ab51b9092c9b87e

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Citations in the corpus

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, neutral): “These data reflect reports of circulating tumor cell clusters associated with poor prognosis in breast and prostate cancer (Aceto et al., 2014), and highlight the need to view cancer as an ecosystem of subclones that may act cooperatively or antagonistically.”
Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis (2015, background): “Their presence could be due to unknown off-target effects of these sgRNAs, random shedding of CTCs in the primary tumor, or clustering together with other strongly selected CTCs during metastasis (Aceto et al., 2014).”
Inflammation and Cancer: Triggers, Mechanisms and Consequences (2019, background): “, 2017), which would precipitate the adherence of metastatic seeds, form complexes with cancer cells and mediate their adhesion and translocation throughout the vessel wall as well as establishing and maintaining the metastatic niche (Aceto et al., 2014; Szczerba et al., 2019; Wolf et al., 2012).”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “CTC clusters introduced experimentally into the venous circulation are far more efficient than individual carcinoma cells in seeding metastatic colonies (Aceto et al., 2014), ostensibly because they are shielded from various types of attacks, such as those launched in the circulation by natural kill”
Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance (2019, background): “Surprisingly, both isolated CTCs and CTC clusters can exhibit epithelial or mesenchymal markers (Aceto et al., 2014).”
Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters (2016, background): “Our findings, in conjunction with recent reports in CTC clusters (5), and genomic sequencing of metastases (7, 8), provide strong evidence for polyclonal seeding as a major mechanism for metastatic spread.”
A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity (2015, neutral): “[76] found that circulating cancer cells (CRCs) can travel in clusters of 2-50 cells and that such CRC clusters can initiate metastatic foci.”
Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis (2015, background): “Third, these cells are likely to be clustered together in the blood and are therefore anoikis-resistant, an essential trait for efficient metastasis (17).”
Dynamic EMT: a multi‐tool for tumor progression (2021, neutral): “Indeed, this type of “collective migration” might be even more common than single-cell dissemination, as supported by several studies using lineage tracing approaches and detection of clustered tumor cells in circulation (Friedl et al , 2012; Aceto et al , 2014; Cheung et al , 2016).”
Liquid Biopsy: From Discovery to Clinical Application. (2021, methodology): “RNA-seq of single CTCs has been used in prostate cancer (20), breast cancer (21, 22), and pancreatic cancer (23) and led to the identification of prognostic signatures, metastatic drivers, and drug target and resistance mechanisms.”