Genetic insights into the morass of metastatic heterogeneity

Abstract

Tumour heterogeneity poses a substantial problem for the clinical management of cancer. Somatic evolution of the cancer genome results in genetically distinct subclones in the primary tumour with different biological properties and therapeutic sensitivities. The problem of heterogeneity is compounded in metastatic disease owing to the complexity of the metastatic process and the multiple biological hurdles that the tumour cell must overcome to establish a clinically overt metastatic lesion. New advances in sequencing technology and clinical sample acquisition are providing insights into the phylogenetic relationship of metastases and primary tumours at the level of somatic tumour genetics while also illuminating fundamental mechanisms of the metastatic process. In addition to somatically acquired genetic heterogeneity in the tumour cells, inherited population-based genetic heterogeneity can profoundly modify metastatic biology and further complicate the development of effective, broadly applicable antimetastatic therapies. Here, we examine how genetic heterogeneity impacts metastatic disease and the implications of current knowledge for future research endeavours and therapeutic interventions.

Fig. 1 |. Models of metastasis evolution and implications of genetic heterogeneity.

a | The classical simple linear model, where clones sequentially arise that dominate the primary tumour owing to survival and proliferative advantages. In this model, metastases arise late in evolution from the most advanced primary tumour clone. b | The early dissemination and parallel evolution model, where tumour cells begin to disseminate early in the primary tumour lifespan and continue to somatically evolve in parallel with the primary tumour during clinical dormancy until they acquire metastatic capacity and proliferate into a clinically relevant lesion. Owing to the independent evolution of the disseminated tumour cells, this model suggests that metastases and primary tumours share only the early tumorigenic driver events. c | The late dissemination model, where tumours evolve over time until a late-arising subclone is able to successfully seed multiple metastases. This model predicts that independent metastases would share the somatic events that occurred during the evolution of the metastatic primary subclone. Subsequently, owing to continuing evolution, individual metastases may diverge somewhat by acquisition of additional subclonal somatic events at the distant site. d | Late dissemination from multiple metastatically competent subclones within the primary tumour. Metastases seeded by this mechanism would share all the somatic events acquired by the tumour preceding the divergence of the different metastatically competent primary tumour subclones. The resulting metastases from the different subclones would be distinguished from each other by the presence of unique somatic events. Blizzard symbol indicates somatic genetic alterations.

Fig. 2 |. Metastatic heterogeneity owing to alternative seeding mechanisms.

a | Polyclonal seeding, where multiple tumour cells from different subclones of the primary tumour disseminate to the secondary site and proliferate in parallel during metastasis evolution. b | Primary tumour reseeding, where metastases are initially generated by a single subclone within the primary tumour. Subsequently, disseminated tumour cells from a different subclone of the primary tumour colonize and proliferate within the already established metastatic lesion. Somatic heterogeneity introduced into the metastasis by this reseeding mechanism would also be present within the primary tumour. c | Metastasis-to-metastasis reseeding, where independent metastases are founded and continue to evolve. A subsequently arising subclone within a metastasis then seeds tumour cells to other metastases. The somatic events that define the metastasis reseeding subclone would not be present in the primary tumour in this mechanism.

Fig. 3 |. The effect of polymorphism on metastatic progression.

a | Mouse mammary tumour virus promoter-driven polyoma middle T oncogene (MMTV-PyMT) male mice were bred to female mice from many different branches of the mouse phylogenetic tree. b | The subsequent F1 progeny have different genetic backgrounds owing to the introduction of a different haploid genome from the maternal strain. Subsequent analysis of the average number of metastases (y axis in the bar chart) in the transgene-positive F1 female progeny revealed that the metastatic capacity of mammary tumours across the different genetic backgrounds varied substantially, with eight strains showing statistically significant differences (red bars) when compared with the original FVB/NJ homozygous genetic background (green bar). c | A minor allele in the promoter of signal-induced proliferation-associated 1 (SIPA1) (homozygous for the allele denoted by the genotype AA (in red)) predicts distant metastasis-free survival (MFS) in the oestrogen receptor-positive (ER⁺) lymph node-negative (LN⁻) subtype of human breast cancer. Parts a and b are adapted from REF. , CC0 1.0. Part c is adapted from REF. , Macmillan Publishers Limited.