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 Lahav, Katerina Politi, Joan S. Brugge () and Aviv Regev ()
Additional contact information
Yaara Oren: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Michael Tsabar: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Michael S. Cuoco: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Liat Amir-Zilberstein: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Heidie F. Cabanos: Massachusetts General Hospital
Jan-Christian Hütter: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Bomiao Hu: Yale School of Medicine
Pratiksha I. Thakore: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Marcin Tabaka: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Charles P. Fulco: Broad Institute of MIT and Harvard
William Colgan: Broad Institute of MIT and Harvard
Brandon M. Cuevas: Klarman Cell Observatory, Broad Institute of MIT and Harvard
Sara A. Hurvitz: University of California, Los Angeles
Dennis J. Slamon: University of California, Los Angeles
Amy Deik: Metabolomics Platform, Broad Institute
Kerry A. Pierce: Metabolomics Platform, Broad Institute
Clary Clish: Metabolomics Platform, Broad Institute
Aaron N. Hata: Massachusetts General Hospital
Elma Zaganjor: Vanderbilt University
Galit Lahav: Harvard Medical School
Katerina Politi: Yale School of Medicine
Joan S. Brugge: Harvard Medical School
Aviv Regev: Klarman Cell Observatory, Broad Institute of MIT and Harvard

Nature, 2021, vol. 596, issue 7873, 576-582

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03796-6

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