Nutrition, ageing and prostate cancer: an experimental approach using Drosophila

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Can nutritional and ageing biology solve the problem of prostate cancer? This project will test this idea using experiments in Drosophila.Prostate cancer (PCa) accounts for more than a quarter of male cancers in the UK, one third of which occur >75yrs. Environmental risk factors are evidenced by worldwide variation in PCa rates and changes in risk when migrants change countries. Among risk factors, nutrition is of particular importance. At a molecular level, it is thought to be linked to mis-regulated mTOR signalling in the mTORC1 nutrient-sensing pathway. Unfortunately, there is little clarity on how these mechanisms connect to cause cancer in vivo, limiting progress. Nutrition and mTOR are known evolutionarily conserved regulators of ageing and age-related disease, and mTOR plays a role in tumour-promoting exosome production. But whether nutrient/mTOR interventions could prevent or reverse PCa remains unclear. To address this multidimensional problem experimentally, we propose to use the functional genetics powerhouse, the fruit fly (Drosophila melanogaster).The PhD's objectives will be to assay the impacts of age and (1) diet, (2) mTORC1 pathway components using genetic manipulations, and (3) drugs that precisely target components of the mTORC1 pathway, on prostate-like cell growth and genome replication in different prostate growth states (benign, PCa, and castration-resistant prostate cancer [CRPC]).The fly system allows for rapid tests of diet, genetic and pharmaceutical interventions in a PCa model. The secondary cells (SCs) of male Drosophila share fundamental features with the human prostate: they make seminal fluid and exosomes, and growth is regulated by steroid-dependent and -independent signals, mirroring healthy prostate and CRPC respectively. SC growth and endoreplication will be assayed in (A) males fed diets that vary in carbohydrates, protein, and fats, including compositions known to extend lifespan, (B) males with mutations affecting mTORC1 signalling, focusing on those known to extend lifespan, and males with SC-specific manipulation of mTORC1 signalling, and (C) males treated with lifespan-extending drugs that target mTORC1 pathway components.This work will address biological complexity of an important health problem in vivo in a whole animal system. It will provide opportunities for future novel or improved interventions, to prevent or ameliorate prostate cancer, as part of wider geroprotection against the multimorbidities of ageing.