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Novel therapeutic approaches against Head and Neck Squamous Cell Carcinoma

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Universitat de Barcelona. Departament de Genètica, Microbiologia i Estadística

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[eng] Head and neck squamous cell carcinoma (HNSCC) is usually diagnosed in advanced stages. The treatment has not changed much on the last decades, being limited to surgery followed by radiotherapy and/or chemotherapy [mainly cisplatin (CDDP) and 5-fluorouracil (5-FU)]. However, the acquisition of chemotherapy resistance is very common, which usually leads to recurrences and metastases. On the other hand, the role of autophagy in HNSCC is not clearly defined. This is the reason why in this thesis we have proposed: 1) to determine the role of autophagy in HNSCC models and its relationship with chemotherapy resistance and other clinical parameters; 2) to identify target proteins involved in the acquisition of chemotherapy resistance in HNSCC models whose modulation of its expression and/or activity could be of clinical and therapeutic interest. From a retrospective immunohistochemistry (IHC) study, we found that the expression of the autophagy markers sequestosome-1 (p62/SQSTM1) and microtubule-associated proteins 1A/1B light chain 3B (LC3), as well as prostate tumor-overexpressed gene 1 protein (PTOV1), could be considered markers of poor clinical prognosis in laryngeal cancer patients. We found overexpression of PTOV1 and the autophagy-related protein 5 (ATG5) in HNSCC biopsy-derived cell lines with innate resistance to CDDP. Likewise, in general, autophagy activation and/or PTOV1 overexpression occurred in three non-metastatic HNSCC cell lines in which resistance to CDDP and 5-FU had previously been generated, as well as in cancer stem cells (CSCs). Furthermore, PTOV1 overexpression induced autophagy in JHU029 laryngeal cell line. Finally, we found that autophagy inhibition with hydroxychloroquine (HCQ), alone or in combination with CDDP or 5-FU, could be an attractive therapeutic alternative for HNSCC patients with chemotherapy resistance. In addition, a comparative proteomic study revealed tetraspanin 1 (TSPAN1) as a target involved in chemotherapy resistance in HNSCC models. In this sense, TSPAN1 depletion decreased cell proliferation, induced apoptosis, and sensitized HNSCC cell lines and biopsy-derived cell lines to chemotherapeutic agents like CDDP and dasatinib. Moreover, TSPAN1 depletion reduced autophagy and blocked the activation of proto-oncogene tyrosine-protein kinase SRC (SRC), protein kinase B (AKT) and mitogen-activated protein kinase (ERK). In addition, TSPAN1 expression was associated to epithelial–mesenchymal transition (EMT) activation in mice tumors and HNSCC patient biopsies. Overall, TSPAN1 inhibition could be a promising therapeutic strategy to improve the current treatment against HNSCC patients.

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Tesis Doctorals - Departament - Genètica, Microbiologia i Estadística

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Novel therapeutic approaches against Head and Neck Squamous Cell Carcinoma