Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding

作者：Sofia Gkountela, Francesc Castro-Giner, Barbara M. Szczerba, Marcus Vetter, Julia Landin, Ramona Scherrer, Ilona Krol, Manuel C. Scheidmann, Christian Beisel, Christian U. Stirnimann, Christian Kurzeder, Viola Heinzelmann‐Schwarz, Christoph Rochlitz, William P. Weber, Nicola Aceto · 发表于：Cell · 年份：2019 · DOI：10.1016/j.cell.2018.11.046 · 被引用次数：834 · 研究领域：Epigenetics and DNA Methylation、Cancer Cells and Metastasis、Cancer Genomics and Diagnostics

The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na + /K + ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.