Genetic and Transcriptional Instability Alters Cancer Cell Line Drug Response

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. We found evidence of extensive clonal diversity across cancer cell lines. We therefore performed comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7, and assessed their response to 321 anti-cancer compounds. We found substantial genetic and transcriptional variation across strains. Similar observations were obtained across strains of multiple additional cell lines, indicating that genomic variation is a general property of cell lines. Importantly, genetic changes were associated with differential activation of gene expression programs, marked differences in cell morphology and proliferation, and strikingly disparate drug response. Over 75% of the compounds that strongly inhibited some of the strains were completely inactive in others. Genomic analyses of single cell-derived clones showed that ongoing instability quickly translated into cell line heterogeneity, while barcoding experiments revealed that mild differences in culture conditions were sufficient to drive cell line diversification. These findings have important implications for cell line culture practices, providing a framework for ensuring the reproducibility of cell line-based research.

* This study has been recently accepted for publication in Nature.