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 AhmedHaiyin 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, Arjun Raj

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish
Pages (from-to)651-659
Number of pages9
JournalNature
Volume620
Issue number7974
DOIs
StatePublished - Jul 2023

Keywords

  • Antineoplastic Agents/pharmacology
  • Clone Cells/drug effects
  • DNA Barcoding, Taxonomic
  • Drug Resistance, Neoplasm/drug effects
  • Humans
  • Neoplasms/drug therapy
  • RNA-Seq
  • Single-Cell Gene Expression Analysis
  • Tumor Cells, Cultured

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