The secret lives of cancer cell lines

Abstract

The extent of genetic and epigenetic diversity between and within patient tumors is being mapped in ever more detail. It is clear that cancer is an evolutionary process in which tumor cell intrinsic and extrinsic forces shape clonal selection. The pre-clinical oncology pipeline uses model systems of human cancer - including mouse models, cell lines, patient-derived organoids and patient-derived xenografts - to study tumor biology and assess the efficacy of putative therapeutic agents. Model systems cannot completely replicate the environment of human tumors and, even within the same cancer model, data are often irreproducible between laboratories. One hypothesis is that ongoing evolutionary processes remain relevant in laboratory models, leading to divergence over time. In a recent edition of Nature, Ben-David and colleagues showed that different stocks of widely used cancer cell lines - a staple of cancer research over many decades - are highly heterogeneous in terms of their genetics, transcriptomics and responses to therapies. The authors find compelling evidence of positive selection based on ongoing mutational processes and chromosomal instability. Thus, the origin, culture conditions and cumulative number of population doublings of cell lines likely influence experimental outcomes. Here, we summarize the key findings of this important study and discuss the practical implications of this work for researchers using cell lines in the laboratory.

Keywords: Cancer; Cell line; Genetic heterogeneity; Tissue culture; Tumor cell line.

Fig. 1.

Genomic diversity in cell line cultures. Cell lines are proliferative cultures of transformed tumor cells derived from patient samples and grown on 2D tissue culture substrates. Selection occurs at multiple levels during cell line derivation: non-cancer cells are excluded and proliferative cells are selected for, leading to a bias for poorly differentiated cells. Ben-David and colleagues provide evidence that cell lines are genomically unstable during propagation with ongoing selection based on environmental factors, such as cell culture media types (Ben-David et al., 2018). This genomic heterogeneity, which arises through both mutational and chromosomal instability processes, alters the transcriptional profile and drug response of cell lines, and might explain how using the same cell lines in different studies can lead to contradictory results.