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..... READ ARTICLE
Nature DOI:10.1038/s41586-021-03796-6
Authors: 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 & Aviv Regev