Time-Series Single-Cell Sequencing Reveals Tumor Clonal Dynamics

Malignant tumors are known to be composed of polyclonal populations of cells, yet defining genetic fitness landscapes in cancers and how they change over time and with treatments has remained difficult. Salehi, Kabeer, and colleagues employed time-series sampling and single-cell whole-genome sequencing of diploid human breast epithelial cell lines and patient-derived breast cancer xenografts and a computational method suited to phylogenetic analysis of single-cell genomic data that can be used to model fitness (specifically, growth trajectories and fitness coefficients) for specific clones using principles of population genetics. After sampling the cultured breast cancer cells—which consisted of TP53–wild-type cells and two distinct branch populations of isogenic TP53-null (TP53^−/−) cells—seven times over 60 generations, it became apparent that lack of p53 was associated with expansion of clones harboring aneuploid genomes, and these aneuploid TP53^−/− cells outcompeted their diploid counterparts. Importantly, amplification of canonical breast cancer–driving oncogenes such as MDM4 and MYC was associated with higher selection coefficients, suggesting greater fitness. Additionally, clonal dynamics and fitness in four patient-derived TP53-mutant xenograft series, with three representing triple-negative breast cancer (TNBC) and one representing HER2⁺ breast cancer, were monitored for 353 to 927 days each. This work revealed that the HER2⁺ breast cancer samples exhibited limited clonal selection in vivo, whereas the TNBC samples bore signs of strong positive selection on at least one clone. However, treatment with cisplatin to gradually induce resistance altered the fitness landscape, with clones undergoing less positive selection in the absence of treatment gaining an advantage during treatment administration, although this effect was reversible when treatment was suspended. Collectively, the results of this study provide deep insight into the genetic mechanisms underpinning clonal evolution and fitness in breast cancer in the presence and absence of treatment and suggest that clonal competition and associated chemotherapeutic fitness costs could be exploited therapeutically.

Salehi S, Kabeer F, Ceglia N, Andronescu M, Williams MJ, Campbell KR, et al. Clonal fitness inferred from time-series modelling of single-cell cancer genomes. Nature 2021 Jun 23 [Epub ahead of print].

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