Format

Send to

Choose Destination
Cell. 2019 Jan 10;176(1-2):98-112.e14. doi: 10.1016/j.cell.2018.11.046.

Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.

Author information

1
Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland.
2
Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland; SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
3
Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland; Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland.
4
Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland; Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
5
Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
6
NEXUS Personalized Health Technologies, ETH Zurich, 8092 Zurich, Switzerland.
7
Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland; Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
8
Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland.
9
Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland.
10
Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
11
Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland. Electronic address: nicola.aceto@unibas.ch.

Abstract

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.

KEYWORDS:

RNA sequencing; bisulfite sequencing; circulating tumor cell clusters; circulating tumor cells; drug screen; proliferation-associated transcription factors; single cell sequencing; stemness-associated transcription factors

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center