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Variability within rare cell states enables multiple paths toward drug resistance
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Journal Article
Variability within rare cell states enables multiple paths toward drug resistance
2021
Overview
Molecular differences between individual cells can lead to dramatic differences in cell fate, such as death versus survival of cancer cells upon drug treatment. These originating differences remain largely hidden due to difficulties in determining precisely what variable molecular features lead to which cellular fates. Thus, we developed Rewind, a methodology that combines genetic barcoding with RNA fluorescence in situ hybridization to directly capture rare cells that give rise to cellular behaviors of interest. Applying Rewind to BRAF
V600E
melanoma, we trace drug-resistant cell fates back to single-cell gene expression differences in their drug-naive precursors (initial frequency of ~1:1,000–1:10,000 cells) and relative persistence of MAP kinase signaling soon after drug treatment. Within this rare subpopulation, we uncover a rich substructure in which molecular differences among several distinct subpopulations predict future differences in phenotypic behavior, such as proliferative capacity of distinct resistant clones after drug treatment. Our results reveal hidden, rare-cell variability that underlies a range of latent phenotypic outcomes upon drug exposure.
A new methodology, Rewind, traces vemurafenib-resistant melanoma back to its initial cell state before drug treatment, creating, effectively, a cellular time machine.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 631/67
/ Analysis
/ Antineoplastic Agents - pharmacology
/ Biomedical and Life Sciences
/ Biomedical Engineering/Biotechnology
/ Cell Survival - drug effects
/ Extracellular Signal-Regulated MAP Kinases - genetics
/ Extracellular Signal-Regulated MAP Kinases - metabolism
/ Fluorescence in situ hybridization
/ Gene Expression Regulation, Neoplastic - drug effects
/ Genes
/ Humans
/ Identification and classification
/ Integrin alpha3 - metabolism
/ Kinases
/ Melanoma
/ Methods
/ RNA
