CRUK Lung Cancer Centre of Excellence, UCL Cancer Institute, University College London, London WC1E 6JD, UK
Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Dis Model Mech. 2018 Nov 16;11(11):dmm037366. doi: 10.1242/dmm.037366.
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.
肿瘤患者内和患者间的遗传和表观遗传多样性的程度正在被更详细地描绘出来。很明显，癌症是一个进化过程，其中肿瘤细胞内在和外在的力量塑造了克隆选择。临床前肿瘤学管道使用人类癌症的模型系统 - 包括小鼠模型、细胞系、患者来源的类器官和患者来源的异种移植物 - 来研究肿瘤生物学并评估潜在治疗药物的疗效。模型系统不能完全复制人类肿瘤的环境，即使在相同的癌症模型中，数据在实验室之间也常常不可重复。一个假设是，持续的进化过程在实验室模型中仍然相关，导致随着时间的推移发生分歧。在《自然》杂志的最近一版中，Ben-David 及其同事表明，广泛使用的癌症细胞系的不同品系 - 几十年来癌症研究的主要内容 - 在遗传学、转录组学和对治疗的反应方面高度异质。作者发现了基于持续突变过程和染色体不稳定性的正选择的令人信服的证据。因此，细胞系的起源、培养条件和群体倍增次数的累积可能会影响实验结果。在这里，我们总结了这项重要研究的关键发现，并讨论了这项工作对实验室中使用细胞系的研究人员的实际意义。
