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Review
. 2021 Jan;124(1):3-12.
doi: 10.1038/s41416-020-01127-6. Epub 2020 Nov 4.

Genomic control of metastasis

Saroor A Patel  1 , Paulo Rodrigues  1 , Ludovic Wesolowski  1 , Sakari Vanharanta  2
Affiliations
Review

Genomic control of metastasis

Saroor A Patel et al. Br J Cancer. 2021 Jan.

Abstract

Metastasis remains the leading cause of cancer-associated mortality, and a detailed understanding of the metastatic process could suggest new therapeutic avenues. However, how metastatic phenotypes arise at the genomic level has remained a major open question in cancer biology. Comparative genetic studies of primary and metastatic cancers have revealed a complex picture of metastatic evolution with diverse temporal patterns and trajectories to dissemination. Whole-genome amplification is associated with metastatic cancer clones, but no metastasis-exclusive driver mutations have emerged. Instead, genetically activated oncogenic pathways that drive tumour initiation and early progression acquire metastatic traits by co-opting physiological programmes from stem cell, developmental and regenerative pathways. The functional consequences of oncogenic driver mutations therefore change via epigenetic mechanisms to promote metastasis. Increasing evidence is starting to uncover the molecular mechanisms that determine how specific oncogenic drivers interact with various physiological programmes, and what triggers their activation in support of metastasis. Detailed insight into the mechanisms that control metastasis is likely to reveal novel opportunities for intervention at different stages of metastatic progression.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Complex temporal patterns and trajectories of metastatic dissemination.
A cell acquires a set of driver mutations to form a primary tumour (PT). Aggressive primary tumour clones invade, circulate and seed secondary sites to form metastases (M) at various timepoints during tumour evolution. Clones leaving early have greater genetic divergence between the primary tumour and metastases (a) compared with  later disseminating clones (c–e). Clones can depart as single circulating tumour cells (CTC) or in clusters to seed monoclonal (b) and polyclonal (d) metastases, respectively. While driver mutations in metastases are the same as in the primary tumour, whole-genome doubling (WGD) is a more frequent genetic feature of metastases. Following seeding and outgrowth at a secondary site, metastatic clones can further disseminate to cross-seed (c), reseed (e) and self-seed, resulting in a complex clonal landscape.
Fig. 2
Fig. 2. Epigenetic mechanisms alter oncogenic signalling in support of metastasis.
Genetically activated pathways and tissue-specific cellular programmes drive oncogenic signalling in primary tumours (left). The phenotypic output of these pathways can change via several epigenetic mechanisms ranging from alterations in DNA methylation (a), chromatin accessibility (b), histone modification states (c) and higher order chromatin conformation (d). As these epigenetic mechanisms are in principle unspecific, the actual phenotypes that emerge are dictated by the oncogenic programmes that are active in the cells. Some of these phenotypes will enhance oncogenic signalling and get selected for. The phenotypic output of the oncogenic pathways that drive primary tumour formation thus evolves via epigenetic alterations to support metastatic cancer phenotypes (right).
Fig. 3
Fig. 3. Epigenetic origins of metastatic transcriptional programmes.
Aberrant activation of developmental and regenerative programmes, mediators of epithelial–mesenchymal transition (EMT), and stem-cell functions in cancer cells can lead to enhanced metastatic fitness (a). Genetic and epigenetic alterations resulting in optimisation of the phenotypic output of already activated oncogenic signalling pathways lead to the acquisition of metastatic traits. In kidney cancer, the output of the VHL–HIF-2A pathway is altered in metastatic clones through nuclear factor (NF)-κB-dependent enhancer co-option (b). Microenvironmental stimuli induce metastatic oncogenic signalling (c, d). The tumour microenvironment is characterised by persistent inflammation, inducing NF-κB activation and the expression of metastasis genes (c). Tumour hypoxia activates HIF1 and HIF2-dependent transcriptional programmes that have been linked to metastatic progression (d).
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