Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

By Kevin J. Cheung, Veena Padmanaban, Vanesa L. Silvestri, Koen Schipper, J. Cohen, Amanda N. Fairchild, M. Gorin, J. Verdone, K. Pienta, Joel S. Bader and 1 more. Proceedings of the National Academy of Sciences of the United States of America, 2016

680 citations recorded by the source corpus.

Significance Conventional models of cancer progression propose that single cells leave the primary tumor, enter the circulation, and seed clonal metastases. However, metastases can contain multiple clones, raising the question: How do polyclonal metastases form? We demonstrate that cancer cells seed distant organs as cohesive clusters, composed of two molecularly distinct subpopulations, whose proportions vary systematically during metastasis. We establish that collective dissemination is a frequent mechanism for metastasis and identify a molecular program in the most invasive, keratin 14+ (K14+) cancer cells, regulating cell–cell adhesion, cell–matrix adhesion, and immune evasion. We demonstrate that this metastatic phenotype is dependent upon K14 expression. Understanding the molecular basis of collective dissemination may therefore enable novel prognostics and therapies to improve patient outcomes. Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14+ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14+ epithelial tumor cell clusters disseminate collectively to colonize distant organs.

Subfields: Cell Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/9e0222aa4f11d52605f7618868fa9f2abd0e283b

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Citations in the corpus

Systems Biology of Cancer Metastasis (2019, background): “Variations typically include genetic perturbations in tumor cells, microenvironmental factors (rigidity, matrix etc.), metabolic environ, as well as presence of soluble factors (Cheung and Ewald, 2016; Cheung et al., 2016; Lehmann et al., 2017; Zanoni et al., 2016). ii.”
Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, neutral): “Evidence for polyclonal seeding of metastases was also observed in a common mouse model of breast cancer (Cheung et al., 2016).”
Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “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).”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “…be further complicated by the fact that metastases have been reported to result from polyclonal populations ostensibly derived from clustered CTCs (Cheung et al., 2016), and by the observation that metastatic clones may be transferred between different metastatic lesions in the same patient…”