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Study Reveals Genomic Evolution Effects on Human Cell Lines

NEW YORK (GenomeWeb) – New research has revealed the extent to which cell lines evolve with time, leading to genetic and gene expression shifts that can change the way these lines respond to anti-cancer compounds and other drugs.

"[C]ancer cell lines remain a powerful tool for cancer research, but their genomic evolution leads to a high degree of variation across cell line strains, which must be considered in experimental design and data interpretation," co-corresponding authors Todd Golub and Rameen Beroukhim of the Broad Institute, Dana-Farber Cancer Institute, and Harvard Medical School, and their colleagues wrote.

As they reported online today in Nature, the researchers considered exome sequence data for 106 human cell lines grown in parallel in labs in the US and UK. From there, they focused in on 27 versions of the same estrogen receptor-positive breast cancer cell line for more extensive genomic profiling, seeing signs of genetic diversification that were echoed in more than a dozen more cell lines.

Such genetic diversification was linked to gene expression shifts, anti-cancer drug responses, and other changes, while the team's barcoding and single-cell analyses pointed to clonal selection and genomic instability that leads to heterozygosity within a line of cells that started out the same.

"Our results show that established cancer cell lines, generally thought to be clonal, are in fact highly genetically heterogeneous," the authors wrote. This heterogeneity, they noted, results both from clonal dynamics, or changes in the abundance of pre-existing subclones, and from continuous instability, or the appearance of new genetic variants.

Although human cell line studies have been instrumental in cancer biology and beyond, the team explained, there are clues — including research reproducibility issues — that suggest such lines may not remain static or stable over time.

"We hypothesized that cancer cell lines are neither clonal nor genetically stable," the authors wrote, "and that this instability can generate variability in drug sensitivity."

To explore that possibility, the researchers used a standardized pipeline to re-analyze exome sequence data for 106 cell lines from the Broad Institute's Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer set from the Sanger Institute.

That comparison uncovered some somatic variant and copy number differences between distinct cultures of individual cell lines, the team reported, prompting more detailed analyses on 27 "strains" from the MCF7 ER-positive breast cancer cell line.

Based on imaging, sequencing, chemical screening, and other analyses, the researchers saw hundreds of genes with copy number gains or losses, as well as point mutations, small insertions or deletions, chromosomal translocations, gene expression, and drug response differences across various versions of MCF7. Similar within-cell line variability turned up when they looked at a dozen other cell lines, including the lung cancer cell line A549.

While the genomic evolution detected raised concerns about the reliability of cell line experiments that do not take this process into account, the study's authors noted that there are also potential benefits to recognizing and harnessing this within-cell line heterogeneity.

They wrote that "deeper characterization … of the heterogeneity within cultures of common cell lines could enable the study of cooperative and competitive interactions between cancer cell populations and mechanisms of pre-existing drug resistance," for example, and "owing to their matched genetic background, naturally occurring 'isogenic-like' strains could help to uncover the association between molecular features and phenotypes such as drug response."