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Single-cell trajectories of melanoma cell resistance to targeted treatment

Cancer Biology & Medicine 2022年第1期19卷 56-73页

作者： Maria Schmidt Lena Sünke Mortensen henry loeffler-wirth Corinna Kosnopfel Knut Krohn Hans Binder Manfred Kunz Interdisciplinary Centre for Bioinformatics University of LeipzigLeipzig 04107Germany Department of Dermatology Venereology and AllergologyUniversity of WürzburgWürzburg 97074Germany Core Unit DNA Technologies Medical FacultyUniversity of LeipzigLeipzig 04103Germany Department of Dermatology Venereology and AllergologyUniversity of Leipzig Medical CenterLeipzig 04103Germany

Objective:Cellular heterogeneity is regarded as a major factor affecting treatment response and resistance in malignant *** developments in single-cell sequencing technology have provided deeper insights into these ***:Here,we analyzed a BRAFV600 E-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 *** 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 ***:Trajectories associated with resistance to single-agent treatment involved cell cycle,extracellular matrix,and de-differentiation *** contrast,shifts detected in double-resistant cells primarily affected translation and mitogen-activated protein kinase pathway reactivation,with a small subpopulation showing markers of *** findings were validated in pseudotime analyses and RNA velocity ***:The single-cell transcriptomic analyses reported here employed a spectrum of bioinformatics methods to identify mechanisms of melanoma resistance to single-and double-agent *** 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.

关键词： Melanoma single-cell transcriptome sequencing treatment response

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