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- Title
Single-cell trajectories of melanoma cell resistance to targeted treatment.
- Authors
Schmidt, Maria; Mortensen, Lena Sünke; Loeffler-Wirth, Henry; Kosnopfel, Corinna; Krohn, Knut; Binder, Hans; Kunz, Manfred
- Abstract
Objective: Cellular heterogeneity is regarded as a major factor affecting treatment response and resistance in malignant melanoma. Recent developments in single-cell sequencing technology have provided deeper insights into these mechanisms. Methods: Here, we analyzed a BRAFV600E-mutant melanoma cell line by single-cell RNA-seq under various conditions: cells sensitive to BRAF inhibition with BRAF inhibitor vemurafenib and cells resistant to BRAF inhibition with vemurafenib alone or vemurafenib in combination with the MEK1/2 inhibitors cobimetinib or trametinib. Dimensionality reduction by t-distributed stochastic neighbor embedding and self-organizing maps identified distinct trajectories of resistance development clearly separating the 4 treatment conditions in cell and gene state space. Results: Trajectories associated with resistance to single-agent treatment involved cell cycle, extracellular matrix, and de-differentiation programs. In contrast, shifts detected in double-resistant cells primarily affected translation and mitogen-activated protein kinase pathway reactivation, with a small subpopulation showing markers of pluripotency. These findings were validated in pseudotime analyses and RNA velocity measurements. Conclusions: The single-cell transcriptomic analyses reported here employed a spectrum of bioinformatics methods to identify mechanisms of melanoma resistance to single- and double-agent treatments. This study deepens our understanding of treatmentinduced cellular reprogramming and plasticity in melanoma cells and identifies targets of potential relevance to the management of treatment resistance.
- Subjects
MITOGEN-activated protein kinases; SELF-organizing maps; MELANOMA; BRAF genes; RNA analysis
- Publication
Cancer Biology & Medicine, 2022, Vol 19, Issue 1, p56
- ISSN
2095-3941
- Publication type
Article
- DOI
10.20892/j.issn.2095-3941.2021.0267