Stroma-induced phenotypic plasticity offers phenotype-specific targeting to improve melanoma treatment

Autor: Thomas Sauter, Eivind Valen Egeland, Kjetil Nordbø Jørgensen, Marco Vincent Haselager, Kotryna Seip, Olav Engebraaten, Gunhild Mari Mælandsmo, Mads H. Haugen, Philippe Lucarelli, Lina Prasmickaite, Marco Albrecht
Přispěvatelé: Experimental Immunology, Graduate School, CCA - Cancer biology and immunology, AII - Cancer immunology
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Cancer Research
Apoptosis
Drug Resistance
Neoplasm/drug effects
Biochemistry
biophysics & molecular biology [F05] [Life sciences]
Drug Screening Assays
Cell Proliferation/drug effects
Neoplasm/drug effects
tumor-stroma interactions
Vemurafenib
Biochimie
biophysique & biologie moléculaire [F05] [Sciences du vivant]
Melanoma
Tumor-stroma interactions
Tumor
Phenotype
Adaptation
Physiological
3. Good health
Physiological/drug effects
Oncology
Antineoplastic Agents/pharmacology
cancer-associated fibroblasts
medicine.drug
Stromal cell
Antineoplastic Agents
Antitumor/methods
Adaptation
Physiological/drug effects
Drug Screening Assays
Antitumor/methods
Biology
Cancer-Associated Fibroblasts/drug effects
Cell Line
Melanoma/genetics
03 medical and health sciences
Stroma
Cell Line
Tumor
medicine
melanoma
Humans
Adaptation
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Phenotype switching
Cancer-associated fibroblasts
Cell Proliferation
drug resistance
VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762
Apoptosis/drug effects
Fibroblasts
medicine.disease
Coculture Techniques
VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762
030104 developmental biology
Fibroblasts/cytology
Drug Resistance
Neoplasm
Protein Kinase Inhibitors/pharmacology
Drug resistance
Cancer cell
Cancer research
Cancer-Associated Fibroblasts
Drug Screening Assays
Antitumor
Zdroj: Cancer Letters
Cancer letters. Ireland (2018).
Cancer letters, 439, 1-13. Elsevier Ireland Ltd
ISSN: 0304-3835
Popis: Cancer cells' phenotypic plasticity, promoted by stromal cells, contributes to intra-tumoral heterogeneity and affects response to therapy. We have disclosed an association between fibroblast-stimulated phenotype switching and resistance to the clinically used BRAF inhibitor (BRAFi) vemurafenib in malignant melanoma, revealing a challenge in targeting the fibroblast-induced phenotype. Here we compared molecular features and drug sensitivity in melanoma cells grown as co-cultures with fibroblasts versus mono-cultures. In the presence of fibroblasts, melanoma cells switched to the dedifferentiated, mesenchymal-like, inflammatory phenotype that showed reduced sensitivity to the most of 275 tested cancer drugs. Fibroblasts, however, sensitized melanoma cells to PI3K inhibitors (PI3Ki) and particularly the inhibitor of GSK3, AR-A014418 (GSK3i), that showed superior efficacy in co-cultures. The proteome changes induced by the BRAFi + GSK3i combination mimicked changes induced by BRAFi in mono-cultures, and GSK3i in co-cultures. This suggests that the single drug drives the response to the combination treatment, depending on fibroblast presence or absence, consequently, phenotype. We propose that the BRAFi and GSK3i (or PI3Ki) combination exemplifies phenotype-specific combinatorial treatment that should be beneficial in phenotypically heterogeneous tumors rich in stromal interactions.
Databáze: OpenAIRE
Externí odkaz: