Cetuximab promotes epithelial to mesenchymal transition and cancer associated fibroblasts in patients with head and neck cancer
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Sandra Schmitz1,2, Gabriela Bindea3,4,5, Roxana Irina Albu1, Bernhard Mlecnik3,4,5 and Jean-Pascal Machiels1,2
1 Institut Roi Albert II, Department of Medical Oncology, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université catholique de Louvain, Brussels, Belgium
2 Department of Head and Neck Surgery, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
3 INSERM UMRS1138, Laboratory of Integrative Cancer Immunology, Paris, France
4 Université Paris Descartes, Rue de l’Ecole de Médecine, Paris, France
5 Cordeliers Research Centre, Université Pierre et Marie Curie Paris, Paris, France
Jean-Pascal Machiels, email:
Keywords: head and neck cancer, epithelial-mesenchymal transition, cancer-associated fibroblasts, anti-EGFR therapy, pharmacodynamic
Received: September 02, 2015 Accepted: September 09, 2015 Published: September 30, 2015
Purpose: To investigate if cetuximab induces epithelial to mesenchymal transition (EMT) and activation of cancer associated fibroblast (CAF) in the tumors of patients with squamous cell carcinoma of the head and neck (SCCHN).
Methods: Cetuximab was administered for two weeks prior to surgery to 20 treatment-naïve patients. Five untreated patients were included as controls. Tumor biopsies were performed at baseline and before surgery. Gene expression profiles and quantitative real-time PCR (qRT-PCR) analysis of the pre-and post-treatment biopsies were compared. To further investigate EMT and CAF, correlations between previously described EMT and CAF markers and our microarray data set were calculated.
Results : Gene expression profile analyses and qRT-PCR showed that some of the genes modified by cetuximab were related to CAFs and EMT (ZNF521, CXCL12, ASPN, OLFML3, OLFM1, TWIST1, LEF1, ZEB1, FAP). We identified 2 patient clusters with different EMT and CAF characteristics. Whereas one cluster showed clear upregulation of expression of genes implicated in CAF and EMT including markers of embryologic pathways like NOTCH and Wnt, the other did not.
Conclusion: Even if EMT and CAFs are implicated in cetuximab resistance in pre-clinical models, we demonstrate for the first time that these molecular processes may occur clinically early on.
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