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Decoding the interplay between genetic and non-genetic drivers of metastasis

Nature volume 629, pages 543–554 (2024)Cite this article

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Abstract

Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs. Although it is now accepted that disseminating tumour cells need to acquire multiple competencies to face the many obstacles they encounter before reaching their metastatic site(s), whether these competencies are acquired through an accumulation of metastasis-specific genetic alterations and/or non-genetic events is often debated. Here we review a growing body of literature highlighting the importance of both genetic and non-genetic reprogramming events during the metastatic cascade, and discuss how genetic and non-genetic processes act in concert to confer metastatic competencies. We also describe how recent technological advances, and in particular the advent of single-cell multi-omics and barcoding approaches, will help to better elucidate the cross-talk between genetic and non-genetic mechanisms of metastasis and ultimately inform innovative paths for the early detection and interception of this lethal process.

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Fig. 1: The three main phases of metastasis.
Fig. 2: The main biological processes that fuel dissemination.
Fig. 3: The MIC phenotype is dictated by the interplay between genotype and plasticity.
Fig. 4: Timing and occurrence of dissemination and dormancy.
Fig. 5: An integrated and dynamic view of the genetic and non-genetic mechanisms underpinning metastasis.

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Acknowledgements

We thank M. Dawson and S. M. Fendt for reading and comments on the manuscript. P.K. received financial support from the Foundation against Cancer (Stichting tegen Kanker, 2021-028). The work from the Marine laboratory that is cited in this review was supported by the FWO (G0C530N and G070622N), Stichting Tegen Kanker (FAF-F/2018/1265), Melanoma Research Alliance (MRA, EIA 623591), KU Leuven (C1 grant) and the Belgian Excellence of Science (EOS) program.

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  1. Laboratory for Molecular Cancer Biology, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium

    Panagiotis Karras & Jean-Christophe Marine

  2. Department of Oncology, KU Leuven, Leuven, Belgium

    Panagiotis Karras & Jean-Christophe Marine

  3. Cancer Genome Evolution Research Group, UCL Cancer Institute, London, UK

    James R. M. Black & Nicholas McGranahan

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P.K. and J.-C.M. conceived the study and supervised its development. P.K., J.-C.M., J.R.M.B. and N.M. contributed to the writing of the paper, edited and provided feedback on all parts. P.K. and J.R.M.B. designed the figures.

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Karras, P., Black, J.R.M., McGranahan, N. et al. Decoding the interplay between genetic and non-genetic drivers of metastasis. Nature 629, 543–554 (2024). https://doi.org/10.1038/s41586-024-07302-6

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