Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells

Yogesh Goyal (), Gianna T. Busch, Maalavika Pillai, Jingxin Li, Ryan H. Boe, Emanuelle I. Grody, Manoj Chelvanambi, Ian P. Dardani, Benjamin Emert, Nicholas Bodkin, Jonas Braun, Dylan Fingerman, Amanpreet Kaur, Naveen Jain, Pavithran T. Ravindran, Ian A. Mellis, Karun Kiani, Gretchen M. Alicea, Mitchell E. Fane, Syeda Subia Ahmed, Haiyin Li, Yeqing Chen, Cedric Chai, Jessica Kaster, Russell G. Witt, Rossana Lazcano, Davis R. Ingram, Sarah B. Johnson, Khalida Wani, Margaret C. Dunagin, Alexander J. Lazar, Ashani T. Weeraratna, Jennifer A. Wargo, Meenhard Herlyn and Arjun Raj ()
Additional contact information
Yogesh Goyal: Northwestern University
Gianna T. Busch: University of Pennsylvania
Maalavika Pillai: Northwestern University
Jingxin Li: University of Pennsylvania
Ryan H. Boe: University of Pennsylvania
Emanuelle I. Grody: Northwestern University
Manoj Chelvanambi: The University of Texas MD Anderson Cancer Center
Ian P. Dardani: University of Pennsylvania
Benjamin Emert: University of Pennsylvania
Nicholas Bodkin: Northwestern University
Jonas Braun: Northwestern University
Dylan Fingerman: The Wistar Institute
Amanpreet Kaur: University of Pennsylvania
Naveen Jain: University of Pennsylvania
Pavithran T. Ravindran: University of Pennsylvania
Ian A. Mellis: University of Pennsylvania
Karun Kiani: University of Pennsylvania
Gretchen M. Alicea: Johns Hopkins School of Public Health
Mitchell E. Fane: Johns Hopkins School of Public Health
Syeda Subia Ahmed: Northwestern University
Haiyin Li: The Wistar Institute
Yeqing Chen: The Wistar Institute
Cedric Chai: Northwestern University
Jessica Kaster: The Wistar Institute
Russell G. Witt: The University of Texas MD Anderson Cancer Center
Rossana Lazcano: The University of Texas MD Anderson Cancer Center
Davis R. Ingram: The University of Texas MD Anderson Cancer Center
Sarah B. Johnson: The University of Texas MD Anderson Cancer Center
Khalida Wani: The University of Texas MD Anderson Cancer Center
Margaret C. Dunagin: University of Pennsylvania
Alexander J. Lazar: The University of Texas MD Anderson Cancer Center
Ashani T. Weeraratna: Johns Hopkins School of Public Health
Jennifer A. Wargo: The University of Texas MD Anderson Cancer Center
Meenhard Herlyn: The Wistar Institute
Arjun Raj: University of Pennsylvania

Nature, 2023, vol. 620, issue 7974, 651-659

Abstract: Abstract Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1–7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7–9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.

Date: 2023
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DOI: 10.1038/s41586-023-06342-8

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