Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.
- Gkountela S Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland.
- Castro-Giner F Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland; SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
- Szczerba BM Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland.
- Vetter M Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland; Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland.
- Landin J Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland; Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
- Scherrer R Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland.
- Krol I Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland.
- Scheidmann MC Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland.
- Beisel C Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland.
- Stirnimann CU NEXUS Personalized Health Technologies, ETH Zurich, 8092 Zurich, Switzerland.
- Kurzeder C Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland; Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
- Heinzelmann-Schwarz V Gynecologic Cancer Center, University Hospital Basel, 4056 Basel, Switzerland.
- Rochlitz C Department of Medical Oncology, University Hospital Basel, 4056 Basel, Switzerland.
- Weber WP Breast Center, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
- Aceto N Cancer Metastasis Laboratory, Department of Biomedicine, University of Basel and University Hospital Basel, 4058 Basel, Switzerland. Electronic address: nicola.aceto@unibas.ch.
- 2019-01-12
Published in:
- Cell. - 2019
RNA sequencing
bisulfite sequencing
circulating tumor cell clusters
circulating tumor cells
drug screen
proliferation-associated transcription factors
single cell sequencing
stemness-associated transcription factors
Animals
Breast Neoplasms
Cell Differentiation
Cell Line, Tumor
Cell Proliferation
DNA Methylation
Disease Models, Animal
Female
Humans
Mice
Mice, Inbred NOD
Nanog Homeobox Protein
Neoplasm Metastasis
Neoplastic Cells, Circulating
Octamer Transcription Factor-3
Repressor Proteins
SOXB1 Transcription Factors
English
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.
- Language
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- English
- Open access status
- hybrid
- Identifiers
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- DOI 10.1016/j.cell.2018.11.046
- PMID 30633912
- Persistent URL
- https://sonar.ch/global/documents/60448
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