Genetic and transcriptional evolution alters cancer cell line drug response.
Genetic and transcriptional evolution alters cancer cell line drug response.
复制标题
DOI：
10.1038/s41586-018-0409-3
复制
发表时间：
2018-08
期刊：
影响因子：
64.8
通讯作者：
Golub TR
中科院分区：
文献类型：
--
作者：
Ben-David U;Siranosian B;Ha G;Tang H;Oren Y;Hinohara K;Strathdee CA;Dempster J;Lyons NJ;Burns R;Nag A;Kugener G;Cimini B;Tsvetkov P;Maruvka YE;O'Rourke R;Garrity A;Tubelli AA;Bandopadhayay P;Tsherniak A;Vazquez F;Wong B;Birger C;Ghandi M;Thorner AR;Bittker JA;Meyerson M;Getz G;Beroukhim R;Golub TR
人类癌细胞系是癌症研究的主力。虽然已知细胞系在培养中进化，但由此产生的遗传和转录异质性及其功能后果的程度仍未得到充分研究。在这里，在两个实验室中生长的106个细胞系的基因组分析揭示了广泛的克隆多样性。对27株常见乳腺癌细胞系MCF7的后续综合基因组表征揭示了快速的遗传多样性。用另外13个细胞系的多个菌株获得了类似的结果。重要的是，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。条形码化实验表明，细胞系进化是由于对培养条件高度敏感的阳性克隆选择而发生的。单细胞衍生克隆的分析表明，持续的不稳定性迅速转化为细胞系异质性。针对321种抗癌化合物的27种MCF7菌株的测试发现了惊人的不同药物反应：至少75%的强烈抑制某些菌株的化合物在其他菌株中完全无活性。这项研究记录了细胞系内遗传变异的程度、起源和后果，并为研究人员提供了一个框架来测量此类变异，以支持最大限度地重复癌症研究。
Human cancer cell lines are the workhorse of cancer research. While cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here, genomic analyses of 106 cell lines grown in two laboratories revealed extensive clonal diversity. Follow-up 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. Importantly, 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 ongoing instability quickly translates into cell line heterogeneity. Testing of the 27 MCF7 strains against 321 anti-cancer compounds uncovered strikingly disparate drug response: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origin and consequence of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.