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Trajectories from Snapshots: Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line

Yapeng Su, Guideng Li, Melissa E. Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Jessica Wang, Jihoon W. Lee, Luke Frankiw, Alexander Xu, Stephanie Wong, Lidia Robert, Kaitlyn Takata, Sui Huang, Antoni Ribas, Raphael Levine, Garry P. Nolan, Wei Wei, Sylvia K. Plevritis, David Baltimore, James R. Heath
doi: https://doi.org/10.1101/767988
Yapeng Su
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
3Institute for Systems Biology, 401 Terry Ave. N., Seattle, WA, USA
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Guideng Li
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
4Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
5Suzhou Institute of Systems Medicine, Suzhou, China
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Melissa E. Ko
6Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA
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Hanjun Cheng
3Institute for Systems Biology, 401 Terry Ave. N., Seattle, WA, USA
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Ronghui Zhu
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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Min Xue
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
14Department of Chemistry, University of California - Riverside, Riverside, CA, USA
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Jessica Wang
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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Jihoon W. Lee
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
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Luke Frankiw
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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Alexander Xu
3Institute for Systems Biology, 401 Terry Ave. N., Seattle, WA, USA
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Stephanie Wong
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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Lidia Robert
7Department of Medicine, University of California – Los Angeles, Los Angeles, CA, USA
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Kaitlyn Takata
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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Sui Huang
3Institute for Systems Biology, 401 Terry Ave. N., Seattle, WA, USA
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Antoni Ribas
7Department of Medicine, University of California – Los Angeles, Los Angeles, CA, USA
8Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
9Department of Surgery, UCLA, Los Angeles, CA, USA
10Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
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Raphael Levine
8Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
10Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
11The Fritz Haber Research Center, The Hebrew University, Jerusalem, Israel
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Garry P. Nolan
12Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
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Wei Wei
3Institute for Systems Biology, 401 Terry Ave. N., Seattle, WA, USA
8Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
10Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
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Sylvia K. Plevritis
13Department of Radiology, Stanford University, Stanford, CA, USA
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David Baltimore
2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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  • For correspondence: baltimo@caltech.edu jheath@systemsbiology.org
James R. Heath
1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
3Institute for Systems Biology, 401 Terry Ave. N., Seattle, WA, USA
8Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA
10Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA
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  • For correspondence: baltimo@caltech.edu jheath@systemsbiology.org
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Abstract

The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge, with relevance towards understanding biological changes ranging from cellular differentiation to epigenetic (adaptive) responses of diseased cells to drugging. We report on a combined experimental and theoretic method for determining the trajectories that specific highly plastic BRAFV600E mutant patient-derived melanoma cancer cells take between drug-naïve and drug-tolerant states. Recent studies have implicated non-genetic, fast-acting resistance mechanisms are activated in these cells following BRAF inhibition. While single-cell highly multiplex omics tools can yield snapshots of the cell state space landscape sampled at any given time point, individual cell trajectories must be inferred from a kinetic series of snapshots, and that inference can be confounded by stochastic cell state switching. Using a microfludic-based single-cell integrated proteomic and metabolic assay, we assayed for a panel of signaling, phenotypic, and metabolic regulators at four time points during the first five days of drug treatment. Dimensional reduction of the resultant data set, coupled with information theoretic analysis, uncovered a complex cell state landscape and identified two distinct paths connecting drug-naïve and drug-tolerant states. Cells are shown to exclusively traverse one of the two pathways depending on the level of the lineage restricted transcription factor MITF in the drug-naïve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities, and are independently druggable. Our results update the paradigm of adaptive resistance development in an isogenic cell population and offer insight into the design of more effective combination therapies.

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Posted September 12, 2019.
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Trajectories from Snapshots: Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line
Yapeng Su, Guideng Li, Melissa E. Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Jessica Wang, Jihoon W. Lee, Luke Frankiw, Alexander Xu, Stephanie Wong, Lidia Robert, Kaitlyn Takata, Sui Huang, Antoni Ribas, Raphael Levine, Garry P. Nolan, Wei Wei, Sylvia K. Plevritis, David Baltimore, James R. Heath
bioRxiv 767988; doi: https://doi.org/10.1101/767988
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Trajectories from Snapshots: Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line
Yapeng Su, Guideng Li, Melissa E. Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Jessica Wang, Jihoon W. Lee, Luke Frankiw, Alexander Xu, Stephanie Wong, Lidia Robert, Kaitlyn Takata, Sui Huang, Antoni Ribas, Raphael Levine, Garry P. Nolan, Wei Wei, Sylvia K. Plevritis, David Baltimore, James R. Heath
bioRxiv 767988; doi: https://doi.org/10.1101/767988

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