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Published June 5, 2019 | Published + Supplemental Material
Journal Article Open

Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance


Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations of drug responses and resistance development. Using BRAF-mutant melanoma cell lines as the prototype, we report on a joint theoretical and experimental investigation of the cell-state transition dynamics associated with BRAF inhibitor drug tolerance. Thermodynamically motivated surprisal analysis of transcriptome data was used to treat the cell population as an entropy maximizing system under the influence of time-dependent constraints. This permits the extraction of an epigenetic potential landscape for drug-induced phenotypic evolution. Single-cell flow cytometry data of the same system were modeled with a modified Fokker-Planck-type kinetic model. The two approaches yield a consistent picture that accounts for the phenotypic heterogeneity observed over the course of drug tolerance development. The results reveal that, in certain plastic cancers, the population heterogeneity and evolution of cell phenotypes may be understood by accounting for the competing interactions of the epigenetic potential landscape and state-dependent cell proliferation. Accounting for such competition permits accurate, experimentally verifiable predictions that can potentially guide the design of effective treatment strategies.

Additional Information

© 2019 Su et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: October 10, 2018; Accepted: April 15, 2019; Published: June 5, 2019. Data Availability Statement: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supporting Information. The RNA-seq raw data reported in this paper have been deposited in the ArrayExpress database (accession no. E-MTAB-5493). This work was supported by NIH (https://www.nih.gov/) grants U54 CA199090 (to AR, JRH, and WW), U01 CA217655 (to AR, JRH, and WW), R35 CA197633 (to AR), Phelps Family Foundation (to WW), and the Jean Perkins Foundation (to JRH). LR was supported by the V Foundation-Gil Nickel Family Endowed Fellowship (https://www.jimmyv.org/), and AHCN was supported by a Banting Fellowship (http://banting.fellowshipsbourses.gc.ca) from the government of Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist. We thank members of the Heath and Wei laboratories for helpful comments on the manuscript. We acknowledge Professor Raphael Levine for helpful discussions regarding the physical models in this paper. Author Contributions: Conceptualization: Yapeng Su, Marcus Bintz, James R. Heath, Wei Wei. Formal analysis: Yapeng Su, Marcus Bintz, Wei Wei. Funding acquisition: Antoni Ribas, James R. Heath, Wei Wei. Investigation: Yapeng Su, Marcus Bintz, Yezi Yang, Alphonsus H. C. Ng, Victoria Liu, Antoni Ribas, James R. Heath, Wei Wei. Methodology: Yapeng Su, Marcus Bintz, Wei Wei. Project administration: James R. Heath, Wei Wei. Resources: Lidia Robert, Antoni Ribas. Supervision: James R. Heath, Wei Wei. Writing – original draft: Yapeng Su, Marcus Bintz, James R. Heath, Wei Wei. Writing – review & editing: Yapeng Su, Marcus Bintz, James R. Heath, Wei Wei.

Attached Files

Published - journal.pcbi.1007034.pdf

Supplemental Material - journal.pcbi.1007034.s001.pdf

Supplemental Material - journal.pcbi.1007034.s002.pdf

Supplemental Material - journal.pcbi.1007034.s003.pdf

Supplemental Material - journal.pcbi.1007034.s004.pdf

Supplemental Material - journal.pcbi.1007034.s005.pdf

Supplemental Material - journal.pcbi.1007034.s006.pdf

Supplemental Material - journal.pcbi.1007034.s007.pdf

Supplemental Material - journal.pcbi.1007034.s008.pdf

Supplemental Material - journal.pcbi.1007034.s009.pdf

Supplemental Material - journal.pcbi.1007034.s010.pdf

Supplemental Material - journal.pcbi.1007034.s011.pdf

Supplemental Material - journal.pcbi.1007034.s012.pdf

Supplemental Material - journal.pcbi.1007034.s013.xlsx

Supplemental Material - journal.pcbi.1007034.s014.xlsx


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August 19, 2023
October 20, 2023