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Queralt, BAuthorGuardeño, RAuthorHernandez-Yague, XAuthorMartin-Castillo, BAuthorBrunet, JAuthorMenendez, JaCorresponding Author

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April 6, 2015
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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

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

Authors: 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.;

Affiliations

Catalan Inst Oncol ICO, Unit Clin Res, Girona, Spain - Author
Catalan Inst Oncol ICO, Unit Translat Res, Girona, Spain - Author
Girona Biomed Res Inst IDIBGi, Girona, Spain - Author

Abstract

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.

Keywords

acquired-resistancebreast-cancer cellscolorectal-cancerde-novo resistancedown-regulationegfr ligandsemtk-ras mutationskraslung-cancerstem cellstgf-betaActin filamentAmphiregulinAntibodies, monoclonalAntigens, cd24Antigens, cd44Antineoplastic agentsArticleBiological markerCancer stem cellCarcinoma, squamous cellCd24 antigenCd44v antigenCell communicationCell differentiationCell line, tumorCell migrationCell populationCetuximabColorectal cancerConcentration responseControlled studyCytoskeletonDna microarrayDown regulationDown-regulationDrug efficacyDrug mechanismDual specificity phosphatase 6Egfr ligandsEmtEnzyme activationEpidermal growth factor receptorEpidermoid tumorEpithelial mesenchymal transitionEpithelial-mesenchymal transitionErlotinibF actinFemaleFlow cytometryGastropodaGefitinibGene regulatory networksGenetic screeningGenetic transcriptionGenome analysisGrowth-factor receptorHumanHuman cellHumansImmunofluorescenceImmunohistochemistryImmunophenotypingIntegrinK ras proteinKeratinKrasLapatinibMetastasisMitogen activated protein kinaseNegative feedbackNeoplasms, squamous cellNucleotide sequenceOccludinPositive feedbackPriority journalProtein expressionProtein phosphorylationProto-oncogene proteinsQuantitative analysisRas proteinsReal time polymerase chain reactionReceptor, epidermal growth factorSignal transductionStem cellsTranscription factor slugTranscription factor snailTranscription regulationTransforming growth factor betaTrastuzumabTumor cellUnindexed sequenceUpregulationUvomorulinVulvar neoplasmsWild type

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Journal Of Cellular Biochemistry due to its progression and the good impact it has achieved in recent years, according to the agency Scopus (SJR), it has become a reference in its field. In the year of publication of the work, 2011, it was in position , thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 3.18, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-17, the following number of citations:

  • WoS: 34
  • Scopus: 41
  • Europe PMC: 24

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-17:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 59.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 59 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 6.

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: MALDEN.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Oliveras-Ferraros, C) and Last Author (Menendez Menendez, Javier Abel).

the authors responsible for correspondence tasks have been Vazquez-Martin, A and Menendez Menendez, Javier Abel.