Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer

Mariangela De Robertis, Luisa Loiacono, Caterina Fusilli, Maria Luana Poeta, Tommaso Mazza, Massimo Sanchez, Luigi Marchionni, Emanuela Signori, Giuseppe Lamorte, Angelo Luigi Vescovi, Jesus Garcia-Foncillas, Vito Michele Fazio

Research output: Contribution to journalArticle

Abstract

Purpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC. Experimental Design: Gene expression analysis was performed in EphA2high cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. Results: We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I-III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Conclusions: These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.

Original languageEnglish (US)
Pages (from-to)159-170
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number1
DOIs
StatePublished - Jan 1 2017

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Colorectal Neoplasms
Gene Expression
EphA2 Receptor
Mutation
Tumor Biomarkers
MicroRNAs
Vascular Endothelial Growth Factor A
Cell Movement
Neoplasms
Research Design
Multivariate Analysis
Cetuximab
Neoplasm Metastasis
Therapeutics
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer. / De Robertis, Mariangela; Loiacono, Luisa; Fusilli, Caterina; Poeta, Maria Luana; Mazza, Tommaso; Sanchez, Massimo; Marchionni, Luigi; Signori, Emanuela; Lamorte, Giuseppe; Vescovi, Angelo Luigi; Garcia-Foncillas, Jesus; Fazio, Vito Michele.

In: Clinical Cancer Research, Vol. 23, No. 1, 01.01.2017, p. 159-170.

Research output: Contribution to journalArticle

De Robertis, M, Loiacono, L, Fusilli, C, Poeta, ML, Mazza, T, Sanchez, M, Marchionni, L, Signori, E, Lamorte, G, Vescovi, AL, Garcia-Foncillas, J & Fazio, VM 2017, 'Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer', Clinical Cancer Research, vol. 23, no. 1, pp. 159-170. https://doi.org/10.1158/1078-0432.CCR-16-0709
De Robertis, Mariangela ; Loiacono, Luisa ; Fusilli, Caterina ; Poeta, Maria Luana ; Mazza, Tommaso ; Sanchez, Massimo ; Marchionni, Luigi ; Signori, Emanuela ; Lamorte, Giuseppe ; Vescovi, Angelo Luigi ; Garcia-Foncillas, Jesus ; Fazio, Vito Michele. / Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 1. pp. 159-170.
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T1 - Dysregulation of EGFR pathway in EphA2 cell subpopulation significantly associates with poor prognosis in colorectal cancer

AU - De Robertis, Mariangela

AU - Loiacono, Luisa

AU - Fusilli, Caterina

AU - Poeta, Maria Luana

AU - Mazza, Tommaso

AU - Sanchez, Massimo

AU - Marchionni, Luigi

AU - Signori, Emanuela

AU - Lamorte, Giuseppe

AU - Vescovi, Angelo Luigi

AU - Garcia-Foncillas, Jesus

AU - Fazio, Vito Michele

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Y1 - 2017/1/1

N2 - Purpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC. Experimental Design: Gene expression analysis was performed in EphA2high cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. Results: We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I-III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Conclusions: These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.

AB - Purpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC. Experimental Design: Gene expression analysis was performed in EphA2high cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response. Results: We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I-III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status. Conclusions: These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations.

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