Cycling cancer persister cells arise from lineages with distinct programs

Yaara Oren, Michael Tsabar, Michael S. Cuoco, Liat Amir-Zilberstein, Heidie F. Cabanos, Jan Christian Hütter, Bomiao Hu, Pratiksha I. Thakore, Marcin Tabaka, Charles P. Fulco, William Colgan, Brandon M. Cuevas, Sara A. Hurvitz, Dennis J. Slamon, Amy Deik, Kerry A. Pierce, Clary Clish, Aaron N. Hata, Elma Zaganjor, Galit LahavKaterina Politi, Joan S. Brugge*, Aviv Regev*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

196 Scopus citations


Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. 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.

Original languageEnglish
Pages (from-to)576-582
Number of pages7
Issue number7873
StatePublished - 26 Aug 2021
Externally publishedYes


FundersFunder number
Breast Cancer Research Foundation-BCRF-16-020
NHGRI Center for Cell Circuits
National Institutes of Health
Howard Hughes Medical Institute
American Cancer SocietyPF-18-126-01-DMC
American Cancer Society
National Cancer InstituteP30CA016042, K08 CA197389, P30 CA016359
National Cancer Institute
National Institute of Allergy and Infectious Diseases1F32AI138458-01
National Institute of Allergy and Infectious Diseases
V Foundation for Cancer ResearchD2015-027
V Foundation for Cancer Research
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation


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