Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Dana-Farber Cancer Institute, Boston, MA, USA.
Nature. 2018 Aug;560(7718):325-330. doi: 10.1038/s41586-018-0409-3. Epub 2018 Aug 8.
Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.
人类癌细胞系是癌症研究的主力军。尽管已知细胞系在培养过程中会发生进化，但由此产生的遗传和转录异质性的程度及其功能后果仍研究不足。在这里，我们使用在两个实验室中生长的 106 个人类细胞系的基因组分析来显示广泛的克隆多样性。对常见乳腺癌细胞系 MCF7 的 27 个菌株的更全面的基因组特征分析揭示了快速的遗传多样化。用 13 个额外细胞系的多个菌株获得了类似的结果。值得注意的是，遗传变化与基因表达程序的差异激活以及细胞形态和增殖的显著差异有关。条形码实验表明，细胞系进化是阳性克隆选择的结果，而这种选择对培养条件非常敏感。对单细胞衍生克隆的分析表明，连续的不稳定性很快转化为细胞系的异质性。当对 27 株 MCF7 进行 321 种抗癌化合物的测试时，我们发现了相当不同的药物反应：至少 75%强烈抑制某些菌株的化合物在其他菌株中完全无效。这项研究记录了细胞系内遗传变异的程度、来源和后果，并为研究人员提供了一个衡量这种变异的框架，以支持最大程度可重复的癌症研究。
