The characterisation of a novel larval Drosophila melanogaster model of cancer cachexia

Cancer cachexia is a common secondary pathology that develops in up to 80% of all late-stage cancer patients. Cachexia is highly deleterious, and leads to the irreversible loss of adipose and muscle tissue in affected patients. The aetiology of cachexia is poorly understood, in part due to the fact it is a highly complex multifactorial condition. Several factors and pathways associated with cachexia have so far been uncovered, but there is a lack of understanding of the key drivers of the pathology and integrated molecular mechanisms that regulate the progression of the disease. It is also unclear whether specific tumour characteristics predispose patients to developing cachexia, resulting in a dearth of early predictive markers for the pathology. As a result there are no convincing preventative or therapeutic options available for patients, and the condition represents an area of unmet clinical need. In this thesis we define a novel model for cancer cachexia in tumour-bearing Drosophila melanogaster larvae. We demonstrate tumour-bearing Drosophila larvae can recapitulate the key human cachectic phenotypes of muscle wasting and intramyocellular lipid droplet formation, as well as many molecular characteristics of the human pathology. The development of cachectic phenotypes in these larvae was dependent on tumour genotype, and not on tumour size, developmental delay, larval bloating, or starvation. These data suggested these animals represented a novel cancer cachexia model, suitable for use in the investigation of molecular mechanisms driving wasting. JAK/STAT signalling is implicated in the onset of cachectic wasting in human patients and model systems. We investigated the role of JAK/STAT signalling, and found that decreasing the activity of JAK/STAT signalling in wasting muscle was sufficient to rescue muscle wasting, and was unexpectedly accompanied by an increase in tumour size. We hypothesise that this may represent a previously unappreciated role of cachexia as a tumour suppressor as a component of the anti-tumour immune response. The data presented in this Thesis suggest tumour-bearing Drosophila larvae represent a novel cachectic model, one that is likely to prove suitable for use in the investigation of host-tumour interactions in the generation of cachexia