Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance
Open accessAbstract
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.
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Schaffer et al. showed that human BRAF mutant melanoma cells exhibit transcriptional heterogeneity at the single-cell level, defining which cells will eventually resist drug therapy.
“Schaffer et al. showed that human BRAF mutant melanoma cells exhibit transcriptional heterogeneity at the single-cell level, defining which cells will eventually resist drug therapy [61].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [61]
Some studies indicate that drug-tolerant persister populations or cancer cells primed to persist exist even prior to treatment.
“Some studies indicate that drug-tolerant persister populations or cancer cells that are primed to persist exist even prior to treatment [40,43,60,61].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [61]
In melanoma, core regulators of neural crest lineage, MITF and SOX10, regulate the emergence of distinct cell states associated with drug tolerance establishment after treatment.
“In melanoma, core regulators of neural crest lineage, MITF and SOX10, regulate the emergence of distinct cell states associated with drug tolerance establishment after treatment [61,82,83,84].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [61]
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- Authors
- Shaffer, S. M., Dunagin, M. C., Torborg, S. R., Torre, E. A., Emert, B., Krepler, C., Beqiri, M., Sproesser, K., Brafford, P. A., Xiao, M., Eggan, E., Anastopoulos, I. N., Vargas-Garcia, C. A., Singh, A., Nathanson, K. L., Herlyn, M., & Raj, A.
- Affiliations
- University of Pennsylvania (US)
- The Wistar Institute (US)
- University of Delaware (US)
- Corresponding author
- Raj, Arjun
- ORCID
- Venue
- Nature
- Published
- 2017-06-15
- Volume
- 546
- Issue
- 7658
- Pages
- 431-435
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5542814
- OpenAlex
- W2621895366
- Cited by
- 1,218
- References
- 34
- Citations by year
- 2026: 115 · 2025: 119 · 2024: 143 · 2023: 148 · 2022: 122 · 2021: 169 · 2020: 160 · 2019: 132 · 2018: 78 · 2017: 32
- FWCI
- 48.45
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-02-21)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (1dp2od008514-01)
- National Human Genome Research Institute (T32HG000046)
- National Cancer Institute (R01CA047159, P01CA114046, U54CA193417, F30-CA254120, P50CA174523, P30CA010815, P30CA016520)
- National Institute of Allergy and Infectious Diseases (F30AI114475)
- National Institute of Biomedical Imaging and Bioengineering (R33EB019767)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- chemoresistance, transcriptional variability, epigenetic reprogramming, melanoma, SOX10, c-Jun, AP-1, TEAD, single-cell transcriptomics, resistance markers, cell differentiation
- MeSH terms
- Vemurafenib, TEA Domain Transcription Factors, Animals, DNA-Binding Proteins, Female, Genetic Markers, Humans, Indoles, Male, Melanoma, Nuclear Proteins, Sulfonamides, Transcription Factors, Transcription, Genetic, Signal Transduction, Gene Expression Regulation, Neoplastic, Oncogene Protein p65(gag-jun), In Situ Hybridization, Fluorescence, Transcription Factor AP-1, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Cell Line, Tumor, SOXE Transcription Factors, Single-Cell Analysis, Cellular Reprogramming, ErbB Receptors
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