Lif as a metabolic messenger: Study of glucose sensing by nsclc and lif-mediated nutrient stress responses
- Autores: Miguel Hernández Madrigal
- Directores de la Tesis: Cristina Muñoz-Pinedo (dir. tes.), Antonio Gentilella (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2022
- Idioma: inglés
- Tribunal Calificador de la Tesis: Ernest Nadal Alforja (presid.), Joan Seoane Suarez (secret.), Carmen Ruiz de Almodovar Egea (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
- Materias:
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- Resumen
Tumours grow in a self-imposed hypoglycaemic microenvironment due to their exacerbated metabolic needs. To thrive in these harsh conditions, malignant cells must adapt their own metabolic routes and hijack the host nutrient supply infrastructure through extracellular signalling.
This study aimed at characterising the secretory response of tumoral cells in response to glucose deprivation, both the molecular signalling leading to this response and the consequences of this response for the tumour. In particular, this study focused on a cytokine never before linked to glucose deprivation: LIF.
Through use of in silico, in vitro, and in vivo approaches we made two novel findings: firstly, we determined that LIF induction happens through non-canonical N-glycosylation dependent signalling, in the context of glucose deprivation. Furthermore, we have determined that the signalling mechanism leading to LIF production encompasses a complex combination of transcriptional and post-transcriptional signals that involve PERK but none of its canonical transcription factors. Secondly, we discovered a novel pro-tumorigenic role for this cytokine as an angiogenic.
Our findings addressed the gap in literature regarding the mechanism for LIF production in tumours, providing insight relevant to future development of therapeutic approaches. And most importantly, we provide an integrative view of not only how glucose deprivation leads to production of LIF, but also how this cytokine could lead to the resolution of the local hypoglycaemia via angiogenesis.
