Abstract
BackgroundTumour progression involves a series of phenotypic changes to cancer cells, each of which presents therapeutic targets. Here, using techniques adapted from microbial experimental evolution, we investigate the evolution of tumour spreading - a precursor for metastasis and tissue invasion - in environments with varied resource supply. Evolutionary theory predicts that competition for resources within a population will select for individuals to move away from a natal site (i.e. disperse), facilitating the colonisation of unexploited resources and decreasing competition between kin.ResultsAfter approximately 100 generations in environments with low resource supply, we find that MCF7 breast cancer spheroids (small in vitro tumours) show increased spreading. Conversely, spreading slows compared to the ancestor where resource supply is high. Common garden experiments confirm that the evolutionary responses differ between selection lines; with lines evolved under low resource supply showing phenotypic plasticity in spheroid spreading rate. These differences in spreading behaviour between selection lines are heritable (stable across multiple generations), and show that the divergently evolved lines differ in their response to resource supply.ConclusionsWe observe dispersal-like behaviour and an increased sensitivity to resource availability in our selection lines, which may be a response to selection, or alternatively may be due to epigenetic changes, provoked by prolonged resource limitation, that have persisted across many cell generations. Different clinical strategies may be needed depending on whether or not tumour progression is due to natural selection. This study highlights the effectiveness of experimental evolution approaches in cancer cell populations and demonstrates how simple model systems might enable us to observe and measure key selective drivers of clinically important traits.
Highlights
Tumour progression involves a series of phenotypic changes to cancer cells, each of which presents therapeutic targets
We found that growth rates of selection lines and ancestor were not different with access to high resource supply (5.0% foetal bovine serum (FBS)) (F2,6 = 1.171; P = 0.372), under low resource supply (0.5% FBS) we find significant differences between ancestral and evolved lines (F2,6 = 17.601; P = 0.003)
A common garden experiment – where evolved lines are grown in both low and high resource environments – reveals that cell populations evolved with a low resource supply show phenotypic plasticity in spheroid spread, such that the rate of spread depends on their current nutrient environment, inducing faster spreading in low resources supply compared to the same population in high resource conditions (Fig. 2)
Summary
Tumour progression involves a series of phenotypic changes to cancer cells, each of which presents therapeutic targets. Using techniques adapted from microbial experimental evolution, we investigate the evolution of tumour spreading - a precursor for metastasis and tissue invasion - in environments with varied resource supply. Once cancer cells become metastatic and move beyond the location of the primary tumour, mortality rates increase drastically [1]. Metastatic and invasive tumours – those that spread beyond the primary location – show increased spreading to adjacent tissues, which is caused by increased cell motility [2]. As such, targeting premetastatic traits might be a novel approach to prevent the evolution of cancerous traits that would facilitate spreading and invasive behaviours [3]. To understand the processes underlying changes in the behaviour of cancerous cells we must first understand the drivers of change
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