Harnessing drosophila pten-deficient cancer to investigate systemic inflammation, dietary interventions, and long-lasting sequelae
- Autores: Ernesto Sáez Carrion
- Directores de la Tesis: María Domínguez Castellano (dir. tes.)
- Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2025
- Idioma: español
- Tribunal Calificador de la Tesis: Javier Morante Oria (presid.), Nuria Paricio Ortiz (secret.), Jorge Bolívar Pérez (voc.)
- Programa de doctorado: Programa de Doctorado en Neurociencias por la Universidad Miguel Hernández de Elche
- Materias:
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- Resumen
Cancer is a complex disease influenced by the host's genetics, hormonal states, metabolism, and sex. Tumour cells exhibit heightened nutrient demands and can remodel their microenvironment and distant organs to support their survival and proliferation. However, the interplay between the cancer's nutrient demands, host metabolism, and host systemic responses-particularly inflammation-remains incomplete. Notably, while dietary restrictions are often suggested to limit nutrient access to cancer cells, Pten-deficient cancers show resistance to these interventions, which can negatively impact the host, leading to higher mortality.
This PhD thesis uses a Drosophila melanogaster Pten-deficient cancer paradigm to explore the connections between cancer, systemic inflammation, and metabolism. We demonstrate that aberrant Nitric Oxide (NO) signalling produced by Pten-deficient tumour cells remotely activates tryptophan (Trp) catabolism to produce Kynurenine (Kyn) metabolites, which promote inflammation and immune suppression in humans. Through genetic, pharmacological, and dietary interventions, we prove the causality of elevated 3-hydroxykynurenine (3-HK) in cancer-inflammation and immune checkpoints, demonstrating for the first time that a host-derived metabolite contributes to cancer and immune suppression.
Additionally, our studies link Trp catabolism to cancer and low-protein diets. The detrimental effects of low-protein diets on hosts with Pten-deficient tumours appear to stem from inflammation tied to Trp metabolism. Our RNA-seq data indicate that dietary restrictions enhance Trp-degrading enzyme activity, promoting tumour growth, particularly in females, who also face more severe cancer-related effects.
Given the gender disparities in cancer incidence and the prevalence of appetite loss and intermittent fasting among patients, our findings highlight the risks associated with such dietary strategies and suggest specific nutritional interventions to target Pten-deficient cancers better.
