Genetic and transcriptional evolution alters cancer cell line drug response

• Published in: Nature (London) Vol. 560; no. 7718; pp. 325 - 330
• Main Authors: Ben-David, Uri, Siranosian, Benjamin, Ha, Gavin, Tang, Helen, Oren, Yaara, Hinohara, Kunihiko, Strathdee, Craig A., Dempster, Joshua, Lyons, Nicholas J., Burns, Robert, Nag, Anwesha, Kugener, Guillaume, Cimini, Beth, Tsvetkov, Peter, Maruvka, Yosef E., O’Rourke, Ryan, Garrity, Anthony, Tubelli, Andrew A., Bandopadhayay, Pratiti, Tsherniak, Aviad, Vazquez, Francisca, Wong, Bang, Birger, Chet, Ghandi, Mahmoud, Thorner, Aaron R., Bittker, Joshua A., Meyerson, Matthew, Getz, Gad, Beroukhim, Rameen, Golub, Todd R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 13/106; 45/22; 45/23; 45/47; 45/90; 45/91; 631/67/69; 631/67/70; Analysis; Biochemistry; Biological evolution; Biotechnology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cancer cells; Cancer research; Cancer therapies; Cell culture; Cell morphology; Cell Proliferation; Cell Shape; Cells (Biology); Clonal selection; Clone Cells - cytology; Clone Cells - drug effects; Clone Cells - metabolism; CRISPR; Cytology; Datasets; Drug metabolism; Evolution; Evolution, Molecular; Gene expression; Genes; Genetic aspects; Genetic diversity; Genetic engineering; Genetic research; Genetic Variation - drug effects; Genetic Variation - genetics; Genomes; Genomic analysis; Genomic Instability - drug effects; Genomic Instability - genetics; Genomics; Heterogeneity; Human behavior; Humanities and Social Sciences; Humans; Instability; Laboratories; MCF-7 Cells; Medical research; Morphology; multidisciplinary; Mutation; Physiological aspects; Reproducibility of Results; Science; Science (multidisciplinary); Stability; Stability analysis; Transcription; Transcription (Genetics); Transcription, Genetic - genetics; Tumor cell lines
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-018-0409-3

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. The extent, origins and consequences of genetic variation within human cell lines are studied, providing a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.