Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency
Open accessAbstract
In metastasis, cancer cells travel around the circulation to colonize distant sites. Due to the rarity of these events, the immediate fates of metastasizing tumor cells (mTCs) are poorly understood while the role of the endothelium as a dissemination interface remains elusive. Using a newly developed combinatorial mTC enrichment approach, we provide a transcriptional blueprint of the early colonization process. Following their arrest at the metastatic site, mTCs were found to either proliferate intravascularly or extravasate, thereby establishing metastatic latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing mTCs to follow the extravasation–latency route. Surprisingly, mTC responsiveness towards niche-derived Wnt was established at the epigenetic level, which predetermined tumor cell behavior. Whereas hypomethylation enabled high Wnt activity leading to metastatic latency, methylated mTCs exhibited low activity and proliferated intravascularly. Collectively the data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche.
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References 74 · Cited by 39
- Authors
- Jakab, M., Lee, K. H., Uvarovskii, A., Ovchinnikova, S., Kulkarni, S. R., Jakab, S., Rostalski, T., Spegg, C., Anders, S., & Augustin, H. G.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Corresponding author
- Jakab, Moritz
- Augustin, Hellmut G.
- ORCID
- Venue
- Nature Cancer
- Published
- 2024-02-02
- Volume
- 5
- Issue
- 5
- Pages
- 716-730
- ISSN
- 2662-1347 (ISSN-L)
- PMC
- PMC11136671
- OpenAlex
- W4391484698
- Cited by
- 39
- References
- 74
- Citations by year
- 2026: 17 · 2025: 13 · 2024: 9
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Cancer (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- Baden-Württemberg Stiftung (CRC1324)
- Deutsches Krebsforschungszentrum
- Francis Crick Institute
- Deutsche Forschungsgemeinschaft (INST35/1503‐1FUGG, CRC 1324, 39404578, 35/1503-1, 35/1503-1 FUGG, 331351713, CRC 1366, INST 35/1503‐1)
- Deutsche Krebshilfe (70114532)
- Klaus Tschira Stiftung (00.022.2019)
- H2020 European Research Council (787181)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- metastatic latency, disseminated tumor cells, lung endothelium, Wnt signaling, angiocrine signaling, DNA methylation, epigenetic regulation, extravasation, metastatic niche, tumor cell fate
- MeSH terms
- Animals, Humans, Lung, Lung Neoplasms, Neoplastic Cells, Circulating, Neoplasm Metastasis, Gene Expression Regulation, Neoplastic, DNA Methylation, Epigenesis, Genetic, Cell Line, Tumor, Cell Proliferation, Wnt Proteins, Mice
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