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Queralt, BAutor o coautorGuardeño, RAutor o coautorHernandez-Yague, XAutor o coautorMartin-Castillo, BAutor o coautorBrunet, JAutor o coautorMenendez, JaAutor (correspondència)

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Stem Cell Property Epithelial-to-Mesenchymal Transition is a Core Transcriptional Network for Predicting Cetuximab (Erbitux (TM)) Efficacy in KRAS Wild-Type Tumor Cells

Publicat a:Journal Of Cellular Biochemistry. 112 (1): 10-29 - 2011-01-01 112(1), DOI: 10.1002/jcb.22952

Autors: Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cufi, Silvia; Queralt, Bernardo; Baez, Luciana; Guardeno, Raquel; Hernandez-Yaguee, Xavier; Martin-Castillo, Begona; Brunet, Joan; Menendez, Javier A.;

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Beyond a well-recognized effect of KRAS mutations in determining de novo inefficacy of cetuximab (CTX) in metastatic colorectal cancer, we urgently need a biomarker signature for predicting CTX efficacy in KRAS wild-type (WT) tumors. CTX-adapted EGFR gene-amplified KRAS WT tumor cell populations were induced by stepwise-chronic exposure of A431 epidermoid cancer cells to CTX. Genome-wide analyses of 44K Agilent's whole human arrays were bioinformatically evaluated by Gene Set Enrichment Analysis (GSEA)-based screening of the KEGG pathway database. Molecular functioning of CTX was found to depend on: (i) The occurrence of a positive feedback loop on Epidermal Growth Factor Receptor (EGFR) activation driven by genes coding for EGFR ligands (e.g., amphiregulin); (ii) the lack of a negative feedback on mitogen-activated protein kinase (MAPK) activation regulated by dual-specificity phosphatases (e.g., DUSP6) and; (iii) the transcriptional status of gene pathways controlling the epithelial-to-mesenchymal transition (EMT) and its reversal (MET) program (actin cytoskeleton and cell-cell communication-e.g., keratins-focal adhesion signaling-e.g., integrins-and EMT-inducing cytokines - e.g., transforming growth factor-?). Quantitative real-time PCR, high-content immunostaining, and flow-cytometry analyses confirmed that CTX efficacy depends on its ability to promote: (i) Stronger cell-cell contacts by up-regulating the expression of the epithelial markers E-cadherin and occludin; (ii) down-regulation of the epithelial transcriptional repressors Zeb, Snail, and Slug accompanied by restoration of cortical F-actin; and (iii) complete prevention of the CD44(pos)/CD24(neg/low) mesenchymal immunophenotype. The impact of EGFR ligands/MAPK phosphatases gene transcripts in predicting CTX efficacy in KRAS WT tumors may be tightly linked with the ability of CTX to concurrently reverse the EMT status, a pivotal property of migrating cancer stem cells.

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