Taylor Tiffany B, Wass Anastasia V, Johnson Louise J, Dash Phil
School of Biological Sciences, University of Reading, Whiteknights, Reading, RG6 6AH, UK.
Milner Centre for Evolution and Department of Biology and Biochemistry, University of Bath, Claverton Down Road, Bath, BA2 7AY, UK.
BMC Evol Biol. 2017 Dec 27;17(1):268. doi: 10.1186/s12862-017-1117-6.
Tumour 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.
After 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.
We 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.
肿瘤进展涉及癌细胞的一系列表型变化，每一种变化都代表着治疗靶点。在此，我们运用从微生物实验进化中借鉴的技术，研究在资源供应各异的环境中肿瘤扩散（转移和组织侵袭的前兆）的进化情况。进化理论预测，种群内对资源的竞争会促使个体离开出生地（即扩散），从而便于开拓未被利用的资源并减少亲属间的竞争。
在资源供应低的环境中经过大约100代培养后，我们发现MCF7乳腺癌球体（小型体外肿瘤）的扩散增加。相反，与资源供应高时的祖先球体相比，扩散速度减慢。共同培养实验证实，不同选择系的进化反应存在差异；在低资源供应条件下进化的系在球体扩散速率方面表现出表型可塑性。选择系之间这些扩散行为的差异具有遗传性（在多代中保持稳定），表明不同进化系对资源供应的反应不同。
我们在选择系中观察到类似扩散的行为以及对资源可用性的敏感性增加，这可能是对选择的反应，也可能是由于长期资源限制引发的表观遗传变化，这些变化在许多细胞代中持续存在。根据肿瘤进展是否由自然选择导致，可能需要不同的临床策略。本研究突出了实验进化方法在癌细胞群体中的有效性，并展示了简单的模型系统如何使我们能够观察和测量临床重要性状的关键选择驱动因素。
