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| Status |
Public on Apr 13, 2017 |
| Title |
Gene expression signature of vemurafenib resistance in WM989 and WM983B melanoma cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Therapies targeting signaling molecules mutated in cancers can often have striking short-term effects, but the emergence of resistant cancer cells is a major barrier to full cures. Resistance can sometimes result from a secondary mutations in rare cells, but other times, there is no clear genetic cause, raising leaving the possibility of non-genetic rare cell variability. Here, we show that melanoma cells can display profound transcriptional variability at the single cell level that predicts which cells will ultimately resist drug treatment. This variability involves 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 an epigenetic reprogramming in these cells, converting the transient transcriptional state to a stably resistant state. This reprogramming begins withis a progressive process consisting of a loss of SOX10-mediated differentiation followed by activation of new signaling pathways, partially mediated by activity of Jun-AP-1 and TEAD. Our work reveals the multistage nature of the acquisition of drug resistance and provides a framework for understanding resistance dynamics. We find that other cell types also exhibit sporadic expression of many of these same marker genes, suggesting the existence of a general rare-cell expression program.
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| |
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| Overall design |
We performed RNA sequencing on WM989 cells without vemurafenib, after 48 hours of treatment, and upon the development of resistance.
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| |
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| Contributor(s) |
Shaffer SM |
| Citation(s) |
28607484 |
| |
| Submission date |
Apr 12, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Sydney M Shaffer |
| E-mail(s) |
sydshaffer@gmail.com
|
| Organization name |
University of Pennsylvania
|
| Street address |
BRB II/III, Room 445, 421 Curie Blvd
|
| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (122)
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| This SubSeries is part of SuperSeries: |
| GSE97682 |
Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance |
|
| Relations |
| BioProject |
PRJNA382674 |
| SRA |
SRP103828 |
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