Program in Systems Biology; Graduate School of Biomedical Sciences
Cancer Biology | Cell Biology
Cancer cells within tumors display a high degree of phenotypic variability. This variability is thought to allow some of the cells to survive and persist after seemingly effective drug treatments. Studies on vemurafenib, a signaling inhibitor that targets an oncogenic BRAF mutation common in melanoma, suggested that cell-to-cell variation in drug resistance, measured by long-term proliferation, originates from epigenetic differences in gene expression that pre-exist treatment. However, it is still unknown whether reactivation of signaling downstream to the inhibited BRAF, thought to be a key step for resistance, is heterogeneous across cells. While previous studies established that signaling reactivation takes place many hours to days after treatment, they monitored reactivation with bulk-population assays unsuitable for detecting cell-to-cell heterogeneity. We hypothesized that signaling reactivation is heterogeneous and is almost instantaneous for a small subpopulation of resistant cells. We tested this hypothesis by monitoring signaling dynamics at a single-cell resolution and observed that despite highly uniform initial inhibition, roughly 15% of cells reactivated signaling within an hour of treatment. Moreover, by tracking cell lineages over multiple days, we established that these cells indeed proliferated more than neighboring cells, thus establishing that rapid signaling reactivation predicts long-term vemurafenib resistance.
Cellular imaging, Cellular noise, Cellular signalling networks, Growth factor signalling, Oncogene proteins, Single-cell imaging, Time series, Tumour heterogeneity, Wide-field fluorescence microscopy
Rights and Permissions
Copyright © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Khoshkenar P, Lowry E, Mitchell A. Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population. Sci Rep. 2021 Jul 29;11(1):15473. doi: 10.1038/s41598-021-94941-8. PMID: 34326399; PMCID: PMC8322260. Link to article on publisher's site
Khoshkenar P, Lowry E, Mitchell A. (2021). Rapid signaling reactivation after targeted BRAF inhibition predicts the proliferation of individual melanoma cells from an isogenic population. Open Access Publications by UMass Chan Authors. https://doi.org/10.1038/s41598-021-94941-8. Retrieved from https://escholarship.umassmed.edu/oapubs/4864
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.