Cancer cell lines evolve genetically and functionally

Cancer cell lines are the backbone of cancer research. In this study, Ben-David and colleagues found that the genetic diversity across multiple samples of the same cancer cell line was much higher than previously appreciated. Anticancer drugs that efficiently kill a cell line in one lab may be completely useless against the same cell line cultured in another lab.

HFSP Long-Term Fellow Uri Ben-David and colleagues
authored on Mon, 10 September 2018

Cancer cell lines are derived from patients’ tumors and propagated in petri dishes in the lab. This important cancer model has been successfully used in cancer research for the past few decades. However, inconsistency and irreproducibility of cancer cell line-based studies raised concerns in the field. It is therefore crucial to understand how cancer cell lines evolve in culture, and how this evolution alters their behavior and their response to chemical and genetic perturbations.

Figure: Genomic evolution in cultured cell lines. Genetic alterations that arise in culture lead to genetic diversification, which in turn leads to transcriptional changes. Consequently, different samples (or 'strains') of the same cancer cell line can respond differently on their exposure to anticancer drugs.

In this study, Uri Ben-David and colleagues studied the genomic, transcriptomic and functional variation across multiple ‘strains’ of several common cancer cell lines. Their study revealed extensive genetic heterogeneity within cultures of cancer cell lines, and demonstrated that this heterogeneity led to genetic diversification of the cell line on prolonged culture. This genetic diversification resulted in global gene expression changes, and striking differences in the response of those cancer cells to drugs. Consequently, two strains of the same cell line cultured in different labs may differ in important ways from one another, potentially leading to substantially distinct results in experiments conducted with the same cell lines in different labs.

The study provides practical recommendations to help researchers cope with cell line evolution. The investigators developed an open, freely-available portal called “Cell STRAINER” (https://cellstrainer.broadinstitute.org/). Using this tool, researchers can compare their own cell line strains to reference strains of the same cell line. This ‘genomic distance’ assessment would help determine whether results obtained with a cell line in one lab could be directly compared to results obtained with the same cell line in another lab. Therefore, the study sheds light on an underappreciated problem in cancer research, and provides practical ways to mitigate the risks associated with it.

Reference

Genetic and transcriptional evolution alters cancer cell line drug response. 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. Nature. 2018 Aug;560(7718):325-330. doi: 10.1038/s41586-018-0409-3. Epub 2018 Aug 8.

PubMed link

Nature cover

Nature editorial

Press release Broad Institute