Rôle de la communication métabolique tumeur-stroma dans la résistance à la thérapie anti-EGFR dans les cancers de la tête et du cou

Details

Supervisors

Corbet, Cyril

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

enHead and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, most often diagnosed at an advanced stage, and associated with a high rate of recurrence. In the recurrent or metastatic setting, therapeutic options remain limited, and median overall survival does not exceed 12–15 months. While immunotherapy has improved the prognosis of PD-L1–positive patients, cetuximab (CTX), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), remains the standard of care for PD-L1–negative patients or following immunotherapy failure. However, its clinical efficacy is frequently compromised by the development of resistance, which does not appear to be driven by specific genetic alterations, thereby directing research efforts toward non-genetic mechanisms, particularly metabolic ones. Recent evidence indicates that lipid metabolic reprogramming plays a key role in tumor progression and therapeutic resistance, both within cancer cells and in their microenvironment, notably through cancer-associated fibroblasts (CAF). This project investigates the hypothesis that CAF contribute to CTX resistance by secreting lipids that protect HNSCC cells from the antibody’s antiproliferative effect. Using 2D and 3D (spheroid) models, we demonstrated that CAF-conditioned medium abolishes the response of HNSCC cells to CTX. The central role of lipids in this process was evidenced by delipidation of the conditioned medium, inhibition of de novo lipogenesis in CAF (TVB-3664), and blockade of fatty acid uptake by tumor cells (SSO). Moreover, CAF and their lipid secretions sustain Erk1/2 phosphorylation in HNSCC cells despite CTX-induced inhibition of EGFR signaling. Finally, lipid complementation experiments suggest that CAF-mediated protection relies on the combined action of fatty acids, cholesterol, and fibroblast-derived factors. Overall, these results highlight the critical role of CAF-secreted factors, particularly lipids, in mediating CTX resistance in HNSCC cells. They underscore the therapeutic potential of targeting metabolic crosstalk between the tumor and its stroma to overcome resistance to CTX in HNSCC.