Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line

Yapeng Su, Melissa E. Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Jessica Wang, Jihoon W. Lee, Luke Frankiw, Alexander Xu, Stephanie Wong, Lidia Robert, Kaitlyn Takata, Dan Yuan, Yue Lu, Sui Huang, Antoni Ribas, Raphael Levine, Garry P. Nolan, Wei Wei, Sylvia K. PlevritisGuideng Li, David Baltimore, James R. Heath*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAFV600E mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.

Original languageEnglish
Article number2345
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020

Bibliographical note

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© 2020, The Author(s).

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