Exploring the effects of diet-induced obesity on the invasiveness of Drosophila tumours

Abstract

Epidemiological studies have shown that obesity promotes cancer development, but whether obesity affects cancer invasion is relatively not well understood. In addition, while cancer is a genetically heterogeneous disease, little is known about whether tumours of different genetic profiles respond differently to obesity. By leveraging the model organism Drosophila melanogaster, this thesis explores (i) whether obesity affects the invasiveness of tumours, and (ii) whether and how different tumours exhibit different invasiveness in response to obesity.

By combining a series of Drosophila models of colorectal cancers with a Drosophila model of diet-induced obesity, I demonstrate that obesity modulates the invasiveness of different tumours to different degrees. Furthermore, I demonstrate that tumours of different genetic profiles respond to obesity with a different directionality depending on the tumour’s pten status; while obesity increased the invasiveness of pten-intact tumours, obesity did not promote the invasiveness of pten-deficient tumours.

Surprisingly, obesity suppressed the invasiveness of rasG12V ptenRNAi tumours. In non-obese animals, rasG12V ptenRNAi tumours exhibited the strongest invasive phenotype; cellular and molecular characterisation revealed that rasG12V ptenRNAi tumours displayed multiple features of epithelial-mesenchymal transition and invaded a specific location in the colorectum. However, obesity reverted these phenotypes, suggesting that obesity significantly and specifically suppresses the invasive properties of rasG12V ptenRNAi tumours.

RNA-Sequencing analysis of rasG12V ptenRNAi tumours revealed increased Reactive Oxygen Species (ROS) as a mediator of obesity-mediated suppression of invasion. I present functional data showing dietary and genetic manipulation to elevate systemic or tumour-specific ROS levels is sufficient to suppress the invasiveness of rasG12V ptenRNAi tumour cells. These results demonstrate an inhibitory role of ROS in the invasiveness of rasG12V ptenRNAi tumours in response to obesity.

Overall, the work presented in this thesis highlights Drosophila as a model system to study the interactions between diet, obesity, and tumour heterogeneity in a whole-animal setting.