Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance

By Sydney M. Shaffer, Margaret C. Dunagin, Stefan R. Torborg, E. Torre, Benjamin L. Emert, C. Krepler, M. Beqiri, Katrin Sproesser, Patricia Brafford, M. Xiao and 7 more. Nature, 2017

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Therapies that target signalling molecules that are mutated in cancers can often have substantial short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures. Resistance can result from secondary mutations, but in other cases there is no clear genetic cause, raising the possibility of non-genetic rare cell variability. Here we show that human melanoma cells can display profound transcriptional variability at the single-cell level that predicts which cells will ultimately resist drug treatment. This variability involves infrequent, semi-coordinated transcription of a number of resistance markers at high levels in a very small percentage of cells. The addition of drug then induces epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state. This reprogramming begins with a loss of SOX10-mediated differentiation followed by activation of new signalling pathways, partially mediated by the activity of the transcription factors JUN and/or AP-1 and TEAD. Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics in single cells. We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general program in which expression is displayed in rare subpopulations of cells.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/b573996695773e5ce9545025208a0feccddb3161

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Citations in the corpus

Learning single-cell perturbation responses using neural optimal transport (2021, background): “, 2014), determined by many factors including the preexisting variability in the abundance and localization of molecular entities, such as RNA or proteins (Shaffer et al., 2017), cellular states (Kramer and Pelkmans, 2019), or the cellular microenvironment (Snijder et al.”
Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity (2020, background): “Vemurafenib Selective BRAF V600E inhibitor (ATP competitive) Activating mutations in NRAS or MEK [23,24]; BRAF/CRAF amplification [23,25]; BRAF alternative splicing [26,27]; RAF heterodimerization [28]; RTK upregulation [29]; Loss of NF1 [30]; COT upregulation [31] Dabrafenib”
Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress (2018, background): “These results match the generally expected trend for methylated promoters to inhibit transcription and are supportive of epigenetic regulation of differentiation as previously appreciated (Lauss et al., 2015; Shaffer et al., 2017).”
Dynamic EMT: a multi‐tool for tumor progression (2021, positive): “…non-small-cell lung cancer (NSCLC), activation of the AXL receptor tyrosine kinase in the course of EMT provides resistance to EGFR and PI3K inhibition, dependent on sustained KRAS activity (Singh et al , 2009; Sequist et al , 2011; Zhang et al , 2012; Byers et al , 2013; Tulchinsky et al , 2019).”
Single-cell RNA sequencing technologies and bioinformatics pipelines (2018, background): “For example, the ability to ﬁ nd and characterize outlier cells within a population has potential implications for furthering our understanding of drug resistance and relapse in cancer treatment 13 .”
SAVER: Gene expression recovery for single-cell RNA sequencing (2018, methodology): “However, we demonstrate later that this can lead to over-smoothing and may remove natural cell-to-cell stochasticity in gene expression, which has been shown to lead to biologically meaningful variations in gene expression, even across cells of the same type or of the same cell line 7–9 .”
Toward Minimal Residual Disease-Directed Therapy in Melanoma. (2018, positive): “…gene expression signature, characterized by low levels of MITF and SOX10 and high levels of AXL, are also intrinsically resistant to MAPK-inhibition (Kemper et al., 2014; Konieczkowski et al., 2014; Müller et al., 2014; Shaffer et al., 2017; Titz et al., 2016; Verfaillie et al., 2015).”
Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “While epigenetic heterogeneity could be key in acquisition of traits of profound clinical importance, such as therapeutic resistance (Shaffer et al., 2017) or metastatic dissemination (Roe et al.”