Journal
CELL
Volume 174, Issue 4, Pages 843-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.06.025
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Categories
Funding
- Omics/Marie Curie@VIB
- KUL GOA [14/012]
- VLK (Vlaamse Liga tegen Kanker)
- Interreg (SKiN-HUID)
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen [G.0929.16N]
- Swedish Research Council
- OHSU Knight Cancer Center Support [NIH P30-CA069533]
- Department of Defense Peer Reviewed Cancer Research Program [W81XWH-15-1-0348]
- V Foundation for Cancer Research [V2015-024]
- Cancer Research Institute and Melanoma Research Alliance
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Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma co-horts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. Those data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.
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