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Evolutionary paths towards metastasis

Nature Reviews Cancer volume 25, pages 545–560 (2025)Cite this article

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Abstract

The evolution of metastasis in humans is considerably less well understood than the biology of early carcinogenesis. For over a century, clinicians and scientists have been debating whether metastatic potential is the intrinsic property of a cancer, pre-determined by the molecular characteristics of the tumour founder cell, or whether metastatic capacity evolves in a stepwise fashion as the tumour grows, akin to the multistage accumulation of oncogenic alterations that give rise to the first cancer cell. In this Perspective, I examine how genetic analyses of primary tumours and matched metastases can distinguish between these two competing metastasis evolution models, with particular emphasis on the utility of metastatic randomness — a quantitative measure that reflects whether metastases arise from a random selection of primary tumour subclones or whether they are enriched for descendants of privileged lineages that have acquired pro-metastatic traits. Probable metastasis evolution trajectories in tumours with high and low baseline metastatic capacity are discussed, along with the role of seeding rates and selection at different metastatic host sites. Finally, I argue that trailblazing insights into human metastasis biology are immediately possible if we make a concerted effort to apply existing experimental and theoretical tools to the right patient cohorts.

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Fig. 1: Two models of metastasis evolution.
Fig. 2: Quantifying metastatic randomness.
Fig. 3: Metastasis evolution in cancers with high and low baseline metastatic potential.
Fig. 4: Genetic divergence between primary tumours and metastases.
Fig. 5: Evolution at the metastatic host site.
Fig. 6: Evolution of late-stage metastatic disease.

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Data availability

Figure 2a shows the replotting of data previously published by Gundem et al.36. Subclone fractions across different lesions are taken directly from Supplementary Table 3. Figure 2b has been redrawn from Figure S14 from Reiter et al.12. Figure 5c,d,e have been redrawn from Fig. 2a,e,h, respectively from Reiter et al.38.

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Acknowledgements

I thank members of the Naxerova lab, M. Nicholson and X. Brunet-Guasch for helpful discussions and for critical reading of the manuscript. This work was supported by the National Cancer Institute of the US National Institutes of Health (R37CA225655, R01CA279054, R01CA26928) and by an Emerging Leader Award from the Mark Foundation for Cancer Research.

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  1. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Kamila Naxerova

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Correspondence to Kamila Naxerova.

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Glossary

Epithelial-to-mesenchymal transition

The process by which cells lose epithelial characteristics (e.g. apicobasal polarity, cell–cell adhesions) and acquire mesenchymal properties (increased motility and invasiveness).

Ferroptosis

Iron-dependent form of cell death.

Genetic drift

The change of allele frequencies in a population over time due to chance alone.

Metachronously

Referring to metastases that are discovered more than 3–6 months after the primary tumour diagnosis.

Microsatellite

DNA sequences composed of short repeats. Microsatellites mutate at higher rates than most other genomic regions.

Peritoneum

The lining of the abdominal cavity which holds in place and protects most abdominal organs, including the intestines.

Synchronously

Referring to metastases that are diagnosed at the same time as the primary tumour.

Variant allele frequencies

Fractions of variant (non-germline) alleles in a tissue sample. The variant allele frequency reflects the proportion of mutant cells in a population.

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Naxerova, K. Evolutionary paths towards metastasis. Nat Rev Cancer 25, 545–560 (2025). https://doi.org/10.1038/s41568-025-00814-x

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