La rigidification de la matrice extracellulaire et la voie de signalisation de l’EGFR coopèrent pour induire l’expansion des carcinomes squameux par la régulation du canal calcique CaV1

Abstract : Epidermal growth factor receptor (EGFR) is a rational target for squamous cell carcinoma (SCC) anticancer therapies, nevertheless; only a subset of patients shows clinical benefits. I demonstrated a cooperation between EGFR signaling and extracellular matrix (ECM) stiffness that could explain this phenomenon. I sought to resolve the molecular pathway underlying this cooperation in SCC proliferation and expansion in order to identify new pharmaceutical targets. Screening of pharmacological inhibitors, in an in vitro 3-D assay, identified verapamil and diltiazem, FDA approved L-type calcium channels inhibitors, as potent blockers of SCC invasion. Mechanistically, I revealed that tumor-derived ECM stiffness and EGFR signaling trigger increased of intracellular calcium through the L-type CaV1.1 channel in SCC. Blocking L-type calcium channels activity resulted in reduced SCC cells invasion and proliferation in vitro. More importantly, I also demonstrate a strong reduction in tumor development in two in vivo models, both head and neck patient derived xenograft and skin SCC mice model. Consequently, I suggest a repurpose of verapamil and diltiazem to anti-cancer agents.
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Eloïse Grasset. La rigidification de la matrice extracellulaire et la voie de signalisation de l’EGFR coopèrent pour induire l’expansion des carcinomes squameux par la régulation du canal calcique CaV1. Sciences agricoles. Université Côte d'Azur, 2017. Français. ⟨NNT : 2017AZUR4091⟩. ⟨tel-02388491⟩

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