Title: Drosophila as a model to study mechanisms of cancer-driven behavioural changes
Funder: Cancer Research UK

Abstract: Background Illness is often accompanied by behavioural changes, which, in the context of a chronic disease, can have extremely deleterious consequences for the host [1, 2]. Cancer is one of the most prevalent illnesses of the modern world. It is estimated that one in two people in the UK will be diagnosed with cancer throughout their lifetime. Anorexia, lack of sleep and disruption of circadian rhythms are often associated with cancer [3-5]. However, very little is known about the mechanisms by which a tumour may impact host central nervous system (CNS) controlled-behaviours. Limitations are mostly imposed by the inherent multifactorial nature of such biological processes and the physiological complexity of conventional animal models of research. Research on the fruit fly Drosophila melanogaster has pioneered behavioural biology [6-8]. Additionally, vast literature has demonstrated the power of Drosophila as a cancer research tool [9, 10]. We propose to use Drosophila to unveil mechanisms by which gut tumours may affect CNS-controlled behaviours in cancer. Aims We hypothesize that intestinal tumours produce secreted factors that remotely control brain function and disrupt regulation of behavioural programs by the CNS. These factors may affect brain function through regulation of enteric neurons, which relay information to the brain and/or by directly acting on neurons within the CNS. To address our hypothesis, we aim to: 1- Assess circadian behaviours, including sleep and feeding in adult Drosophila models of colorectal cancer-like intestinal hyperplasia. 2- Identify gut-derived factors, which may be responsible for changes in behaviour. Methods Model system: We will use genetically defined adult Drosophila models of intestinal hyperplasia, which have proven extremely useful for the identification of conserved mechanisms driving colorectal cancer (CRC) [11-14]. Experimental approach: Aim 1- We will collaborate with experts in Drosophila behavioural biology to quantitatively measure sleep and feeding behaviours in fly models of CRC. Aim 2- We will use genetic tools to manipulate selected candidate secreted factors from the gut and their cognate receptors from neurons and assess the impact in sleeping and feeding behaviours. Long term impact of the research: Results from our research may contribute to improvement of the overall quality of life of cancer patients, including increasing the response to conventional cancer therapies, and the prevention of highly detrimental cancer associated syndromes such as cachexia and emotional disorders.

Lay abstract: Background Illness is often accompanied by behavioural changes, which, in the context of a chronic disease, can have extremely deleterious consequences for the host. Cancer is one of the most prevalent illnesses of the modern world. It is estimated that one in two people in the UK will be diagnosed with cancer throughout their lifetime. Anorexia, lack of sleep and disruption of circadian rhythms are often associated with cancer. However, very little is known about the mechanisms by which a tumour may impact host central nervous system (CNS) controlled-behaviours. Limitations are mostly imposed by the inherent multifactorial nature of such biological processes and the physiological complexity of conventional animal models of research. Research on the fruit fly Drosophila melanogaster has pioneered behavioural biology. Additionally, vast literature has demonstrated the power of Drosophila as a cancer research tool. We propose to use Drosophila to unveil mechanisms by which gut tumours may affect CNS-controlled behaviours in cancer. Aims We hypothesize that intestinal tumours produce secreted factors that remotely control brain function and disrupt regulation of behavioural programs by the CNS. These factors may affect brain function through regulation of enteric neurons, which relay information to the brain and/or by directly acting on neurons within the CNS. To address our hypothesis, we aim to: 1- Assess circadian behaviours, including sleep and feeding in adult Drosophila models of colorectal cancer-like intestinal hyperplasia. 2- Identify gut-derived factors, which may be responsible for changes in behaviour. Methods Model system: We will use genetically defined adult Drosophila models of intestinal hyperplasia, which have proven extremely useful for the identification of conserved mechanisms driving colorectal cancer (CRC). Experimental approach: Aim 1-We will collaborate with experts in Drosophila behavioural biology to quantitatively measure sleep and feeding behaviours in fly models of CRC. Aim 2- We will use genetic tools to manipulate selected candidate secreted factors from the gut and their cognate receptors from neurons and assess the impact in sleeping and feeding behaviours. Long term impact of the research: Results from our research may contribute to improvement of the overall quality of life of cancer patients, including increasing the response to conventional cancer therapies, and the prevention of highly detrimental cancer associated syndromes such as cachexia and emotional disorders.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS