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Using tumour phylogenetics to identify the roots of metastasis in humans

Key Points

  • Whether metastasis tends to occur early or late in tumour development remains controversial, and whether metastases descend directly from the primary tumour or give rise to each other is unclear

  • In the linear progression model, metastatic precursors leave the primary tumour at late stages of disease, after clonal evolution has given rise to a cell with metastatic ability; consequently, primary tumours and metastases are genetically closely related

  • The parallel progression model, on the other hand, assumes that metastasis occurs in early stages of carcinogenesis, and that metastases and primary tumour evolve independently, resulting in genetic disparity between them

  • Comparative genomics studies in different cancer types illustrate a variety of possible progression trajectories for systemic disease, but analysis of more patients is needed to arrive at generalizable conclusions

  • Problems complicating the interpretation of comparative genetics data include the unknown contributions of the tissue-specific background mutational burden, self-seeding and tumour-cell dormancy, and the extensive heterogeneity of primary tumours

  • A variety of experimental approaches beyond next-generation DNA sequencing are available for lineage tracing in human cancer

Abstract

In cancer, much uncertainty remains regarding the origins of metastatic disease. Models of metastatic progression offer competing views on when dissemination occurs (at an early or late stage of tumour development), whether metastases at different sites arise independently and directly from the primary tumour or give rise to each other, and whether dynamic cell exchange occurs between synchronously growing lesions. Although it is probable that many routes can lead to the establishment of systemic disease, clinical observations suggest that distinct modes of metastasis might prevail in different tumour types. Gaining a more-comprehensive understanding of the evolutionary processes that underlie metastasis is not only relevant from a basic biological perspective, but also has profound clinical implications. The 'tree of life' of metastatic cancer contains answers to many outstanding questions about the development of systemic disease, but has only been reconstructed in a limited number of patients. Here we review available data on the phylogenetic relationships between primary solid tumours and their metastases, and examine to what degree they support different models of metastatic progression. We provide a description of experimental methods for lineage tracing in human cancer, ranging from broad DNA-sequencing approaches to more-targeted techniques, and discuss their respective benefits and caveats. Finally, we propose future research questions in the area of cancer phylogenetics.

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Figure 1: Overview of human metastasis models.
Figure 2: The mutational burden of the tumour founder cell might affect interpretation of data from comparative genetics studies.
Figure 3: Using intermediate subclones to search for evidence of tumour self-seeding.
Figure 4: The challenge of proving the parallel progression model of metastasis.

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Acknowledgements

The work of the authors is supported in part by funding from the US Department of Defence (grant W81XWH-11-1-0146 to K.N.), the Breast Cancer Innovator Award (grant W81XWH-10-1-0016 to R.K.J.), the US National Institutes of Health (grants P01CA080124 and R01CA163815 to R.K.J.), the Proton Beam/Federal Share Program (R.K.J.), and the National Foundation for Cancer Research (R.K.J.).

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K.N. and R.K.J. made substantial contributions to discussion of content and review/editing of the manuscript before submission. K.N. researched the data for the article and wrote the manuscript.

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Correspondence to Kamila Naxerova.

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Naxerova, K., Jain, R. Using tumour phylogenetics to identify the roots of metastasis in humans. Nat Rev Clin Oncol 12, 258–272 (2015). https://doi.org/10.1038/nrclinonc.2014.238

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