Genetic and transcriptional evolution alters cancer cell line drug response

Abstract

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.

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

“…To assess whether these observations are due to alterations in ER chromatin binding in KDM5IR cells, we performed ER ChIP-seq before and after E2 stimulation. MCF7 cells cultured in estrogen-depleted conditions had very few ER binding peaks with a dramatic increase 45 min after E2 stimulation (Figure 4G), which is consistent with previous studies (Figure S4G), although, as expected, some variability was observed among different batches of MCF7 cells (Ben-David et al, 2018). In contrast, in KDM5IR cells a subset of ER binding peaks (cluster 1) was present even in estrogen-depleted conditions and increased to a much higher level after E2-treatment than what was observed in parental cells (Figure 4G).…”

Modeling Nanocarrier Transport across a 3D In Vitro Human Blood‐Brain–Barrier Microvasculature

“…However, the use of iPSC‐ECs for developing patient‐specific in vitro models can encourage further investigations that clarify these differences. [ 68 ] Therefore, the here‐proposed methodology could contribute toward a better understanding of disease‐specific transport processes and signaling molecular pathways, potentially leading to the discovery of new targets and candidate membrane transporters to enable improved drug delivery across the BBB.…”

Chrysophanol: a review of its pharmacology, toxicity and pharmacokinetics

“…It was found that chrysophanol had little effect on breast cancer cell lines (MCF‐7, T47D) and colon cancer cell line (HCT‐116) . In view of the huge differences in the apoptosis of the same cancer cells (HepG2 cells) induced by chrysophanol, based on the literature review, we believe that in the case of eliminating human error and differences of experimental conditions, it may be the different degrees of genetic variation occurred in the process of subculture of the same type of cancer cells in the laboratory . Next, the researchers investigated the mechanism of chrysophanol‐induced apoptosis in cancer cells.…”