Characterization of rare-cell expression variability contributing to vemurafenib resistance
Benjamin Emert1,2, Sydney Shaffer1,3,Eduardo A. Torre1,3, Arjun Raj3,4
1Perelman School of Medicine, University of Pennsylvania; 2Genomics and Computational Biology Group, University of Pennsylvania; 3Department of Bioengineering, University of Pennsylvania; 4Department of Genetics, University of Pennsylvania
Rare cell behavior contributes to population phenotypic heterogeneity.In the case of bacterial persistence and cancer, rare single cell variability contributes to therapy resistance. Notably, resistance phenotypes can be inherited across cell lineages in the absence of genetic variation or mutation, allowing for selection of advantageous phenotypes. In melanoma, chemotherapy resistance is linked to single cell differences in gene expression suggesting that altered gene regulation may underlie such phenomenon.Specifically, 0.5%-1.0% melanoma cells express high levels of known resistance markers, including EGFR, NGFR and AXL, prior to exposure to vemurafenib. While conferring a stable selective advantage in the presence of vemurafenib, expression of these resistance genes is transient over the timescale of weeks. To better characterize the gene regulatory network underlying this rare cell behavior, we performed RNA-sequencing on untreated melanoma cells expressing the highest levels of EGFR, NGFR, and AXL. Gene ontology and KEGG pathway analysis revealed signatures of EMT, cell motility and ECM interactions in EGFR and NGFR positive cells. Furthermore, open chromatin near differentially expressed genes in EGFR positive cells are enriched for EZH2 ChIP peaks, consistent with a role for histone modification in single-cell expression variability. In contrast, analyses of AXL positive cells indicate altered regulation of cell-cycle genes. These data and future characterization of additional cell types may reveal common regulators of gene expression variability.
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