Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition

Autor: Christoph Schwärzler, Sylvain Lemeille, Wolf-Henning Boehncke, Hedwig Sutterlüty-Fall, Marylise Fernandez, Rastine Merat
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
Indoles
medicine.medical_treatment
Gene Expression
ddc:616.07
Targeted therapy
ELAV-Like Protein 1
Cell Proliferation/drug effects
single-cell mass cytometry
Melanoma/drug therapy/genetics/metabolism
Mice
ELAV-Like Protein 1/genetics
Transduction
Genetic
Gene expression
Molecular Targeted Therapy
Vemurafenib
Cancer Biology
ddc:616
Sulfonamides
Tumor
Cell Death
Indoles/pharmacology
Melanoma
Adaptive response
targeted therapy
Genetic Vectors/genetics
Oncology
Cell Cycle Checkpoints/drug effects/genetics
medicine.drug
BRAF inhibitor
Proto-Oncogene Proteins B-raf
cell heterogeneity
Sulfonamides/pharmacology
RNA‐binding protein HuR
Genetic Vectors
Short Report
Biology
Adenoviridae
Cell Line
Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/metabolism
03 medical and health sciences
Protein Kinase Inhibitors/pharmacology/therapeutic use
Transduction
Antigen
Genetic
single‐cell mass cytometry
Cell Line
Tumor
medicine
melanoma
Animals
Humans
Radiology
Nuclear Medicine and imaging
Mass cytometry
Cell Death/drug effects/genetics
Adenoviridae/genetics
Protein Kinase Inhibitors
Cell Proliferation
Animal
Cell subpopulations
Cell Cycle Checkpoints
medicine.disease
Xenograft Model Antitumor Assays
Disease Models
Animal
030104 developmental biology
Immunology
Disease Models
Cancer research
RNA-binding protein HuR
Zdroj: Cancer Medicine, Vol. 6, No 7 (2017) pp. 1652-1664
Cancer Medicine
ISSN: 2045-7634
Popis: Tumor plasticity and the heterogeneous response of melanoma cells to targeted therapies are major limits for the long‐term efficacy of this line of therapy. Targeting tumor plasticity is theoretically possible through the modulation of the expression of RNA‐binding proteins which can affect many different compensatory mechanisms of the adaptive response of malignant cells to targeted therapies. Human antigen R (HuR) is a modulator of gene expression and a transacting factor in the mRNA‐processing machinery used in the cell stress response, and is a potential target for reducing tumor plasticity. In this experiment, we exploit the inherent heterogeneous response of the A375 melanoma line to suboptimal BRAF inhibition as a model of immediate adaptive response. We first observe that HuR overexpression can prevent the heterogeneous response and thus the immediate paradoxical proliferation induced by low‐doses vemurafenib treatment. We then use single‐cell mass cytometry to characterize subpopulations, including those that paradoxically proliferate, based on their proliferation rate and the expression patterns of markers involved in the reversible adaptive resistance to BRAF inhibition and/or recognized as HuR targets involved in cell cycle regulation. Under suboptimal BRAF inhibition, HuR overexpression affects these subpopulations and their expression pattern with contrasting responses depending on their proliferation rate: faster‐proliferating vemurafenib‐sensitive or ‐resistant subpopulations showed higher death tendency and reduced size, and slower‐proliferating subpopulations showed an attenuated resistant expression response and their paradoxical proliferation was inhibited. These observations pave the way to new therapeutic strategies for preventing the heterogeneous response of tumors to targeted therapies.
Databáze: OpenAIRE
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