Role of matrix stiffness in the resistance of squamous cell carcinoma cells to anticancer therapies

Abstract : Resistance to epidermal growth factor receptor (EGFR) targeted therapy triggered by the tumor niche in head and neck squamous cell carcinoma (HNSCC) represents a challenge in research and in clinics. Despite the fact that over 15% of HNSCC overexpress EGFR, HNSCC are refractory to EGFR Tyrosine Kinase Inhibitors (TKIs) targeted therapy and yet the molecular and cellular mechanisms of EGFR-TKIs resistance in HNSCC are unknown. The tumor niche plays an important role in conventional chemotherapeutic resistance. Cancer associated fibroblasts (CAFs), the most prominent stromal cell in tumor niche, participate in this process. Notably, CAFs are responsible for tumor tissue fibrosis an excessive extracellular matrix (ECM) remodeling that increases matrix stiffness. In carcinoma cells, adhesion to stiff substrate triggers mechano-dependent intracellular signaling pathways that favor tumor resistance to conventional chemotherapies. My work demonstrates that ECM stiffening is responsible for a significant increase of squamous cell carcinoma (SCC) survival upon the treatment with EGFR TKIs, conventional chemotherapies and combination of both. Over 60% more cells survive treatment with the gefitinib EGFR TKI compared to cells plated on soft matrix. Same effect was observed on matrix derived from CAFs that is known to be stiffer compared to the one derived from fibroblasts isolated from normal skin. Further analysis revealed an induction of partial epidermal-to-mesenchymal transition (EMT) in cells plated on rigid matrices. EMT is know to play a role in resistance of cancer cells to treatments, and I have demonstrated that downregulation of know transcriptional factors involved in EMT leads to an increase of cell susceptibility to EGFR TKI when plated on stiff matrix. To understand in more detail what drives the resistance of SCC cells when plated on stiff we conduced an RNA sequencing. RNA sequencing of SCC12 cells plated on soft and stiff matrix revealed AXL as main driver of EGFR TKI resistance in HNSCC. I was able to demonstrated that inhibiting AXL in SCC cells, lying on stiff matrices, reverts the EGFR TKI resistance triggered by the tumor niche. Moreover, I show in 3D cell culture the importance of combining AXL and EGFR TKI in treatment of SCCs. Our overall goal was to identify novel therapeutic targets with reduced resistance opportunity. Finally, research presented in this manuscript carries potential in establishing a prediction biomarker to the response of HNSCCs and other cancers to EGFR TKIs.
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Sanya-Eduarda Kužet. Role of matrix stiffness in the resistance of squamous cell carcinoma cells to anticancer therapies. Cell Behavior [q-bio.CB]. Université Côte d'Azur, 2019. English. ⟨NNT : 2019AZUR4010⟩. ⟨tel-02477360⟩

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