Impacte d’alteracions metabòliques associades a l'obesitat sobre el paper de la survivina en càncer

Identificador:  TDX:4143

Handle: https://hdl.handle.net/20.500.11797/TDX4143

Autors:  Benaiges Moragrega, Ester

Resum:
Survivin is a multifunctional protein, historically associated with tumoral processes and embryonic development that regulates cellular proliferation and apoptosis. Although its function in cancer is widely studied, its implication with other pathologies is not well defined. In fact, recent studies suggest that survivin might have an important role in the physiopathology of obesity, a metabolic pathology with high prevalence and an acknowledged risk factor for development of different types of cancer. This doctoral thesis is focused on identifying the role of survivin in the relationship between the cells from the tumor microenvironment, namely, adipose-derived stem cells (ASCs), macrophages and tumoral cells in the context of obesity. We also analyze the role of survivin in the progression and response to radiotherapy of patients with head and neck squamous carcinoma (HNSCC) and its relationship with the metabolic state. We show that survivin from ASCs’ secretome of patients with obesity promotes protumoral polarization of macrophages, which are both capable of internalize and secrete survivin. We find that survivin activates a hybrid phenotype of macrophages and promotes their protumoral activity with dependence of the phosphorylation in Threonine 34. Importantly, we establish survivin as a new molecular link between ASCs, macrophages, and tumor cells, as well as a new specific marker of tumor-associated macrophages. In the context of HNSCC, we associate survivin expression in tumoral mucosa with recurrence risk, treatment response and circulating glucose in patients with HNSCC. In an in vitro model we demonstrate that survivin expression regulated by radiation in low-medium radioresistant cells is associated with a protumoral phenotype. We also find that high glucose levels inhibit survivin regulation by radiation and increase cells sensitivity to apoptosis.