Journal
NATURE
Volume 596, Issue 7873, Pages 576-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03796-6
Keywords
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Funding
- Hope Fund for Cancer Research
- Rivkin Scientific Scholar Award
- American Cancer Society-New England Pay-ifGroup Postdoctoral Fellowship [PF-18-126-01-DMC]
- V Foundation Scholar Award [D2015-027]
- NIH F32 Postdoctoral Fellowship from National Institute of Allergy and Infectious Disease [1F32AI138458-01]
- Sanofi
- GlaxoSmithKline
- NIH/NCI [K08 CA197389]
- NCI/NIH [CA016042]
- Marni Levine Memorial Research Award
- Lo Graduate Fellowship for Excellence in Stem Cell Research
- NIH/NCI Cancer Center Support Grant [P30 CA016359]
- Klarman Cell Observatory
- NHGRI Center for Cell Circuits
- Howard Hughes Medical Institute
- Breast Cancer Research Foundation [BCRF-16-020]
- Sheldon and Miriam Adelson Medical Research Foundation
- Grillo-Marxuach Postdoctoral Fellowship
- [R01CA121210]
- [R01CA120247]
- [P50CA196530]
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Recent studies have revealed that cancer cells can enter different lineages in response to treatment, with distinct biological characteristics and metabolic programs. Proliferative capacity of drug-tolerant persister cells is associated with upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation.
Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure(1), where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment(2). Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell's clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.
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