Cancer is one of the most prevalent human killer diseases. Autophagy, a lysosome-mediated process that degrades cellular components and damaged organelles, has recently emerged as an important player in cancer. Indeed, autophagy inhibition promotes cancer initiation through generation of genomic instability and inflammation, whereas in contrast, autophagy activation is often required to sustain growth of advanced solid tumours in a nutrient-deprived hypoxic environment. Recent findings firmly demonstrate that modulating autophagy can potentially be exploited to suppress tumours and to avoid resistance in anti-cancer therapy. However, the interplay between cancer and autophagy is complex, and further in-depth investigation is urgently required. Therefore I propose to use the well-described cancer models in Drosophila, together with the autophagy mutants that I have developed, firstly to test how an autophagy-proficient/deficient host environment alters growth and dissemination of allografted tumours. Secondly, I will examine how modulation of autophagy within the tumour can impact on its growth. In order to alter independently tumour induction with autophagy inhibition/activation, I will make use of the two inducible expression systems currently only available for Drosophila. These experiments will be accompanied by detailed analysis of mitochondrial status, as well as protein damage and DNA lesions, which will shed light on the intricate mechanisms whereby autophagy affects cancer and will help indicate optimal time points for further analysis of the tumours by in-depth transcriptional, proteomic and metabolomic profiling. Collectively, this project proposal is designed to rapidly test various hypotheses for cancer prevention and treatment, to provide valuable insights for further validation in higher organisms, and to identify new potential drug targets for cancer research.
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