Cancer as a systemic disease: Investigating tumour-host interaction in drosophila

Abstract

A complex and bi-directional interaction exists between a tumour and its host. By treating cancer as a systemic disease, and leveraging the genetic tractability of Drosophila melanogaster, work throughout this thesis explores the nature of the tumour-host interaction. By combining Drosophila models of high sugar diet (HSD)-induced obesity and Ras/Src-driven tumourigenesis, I have established a model of ‘cachexia-like’ systemic muscle wasting. This model system has provided an excellent opportunity to explore the metabolic/nutritional interplay between tumourigenesis, HSD-induced obesity, and host systemic muscle wasting. This thesis specifically addresses two questions. Firstly, how does a tumour impact host systemic metabolism? And secondly, how do host metabolic alterations and their associated effects on systemic nutrient availability, impact tumour growth? I identify Branchless (Bnl), a Drosophila Fibroblast Growth Factor (FGF), as a tumour- and hostderived mediator of systemic muscle wasting. I highlight a perturbed systemic metabolic profile, characterised by amino acid mobilisation and elevated levels of circulating amino acids as one of the key consequences of systemic muscle wasting. This altered systemic amino acid profile has functional effects on tumour growth; elevated levels of circulating L-proline promote tumour growth via tumour-autonomous SLC36-family amino acid transporter expression. This establishes a tumour-host circuitry which requires two levels of coordination: (i) at the whole organism level— by promoting cachexia-like muscle wasting and systemic amino acid availability, and (ii) at the tumour-autonomous level—by modulating amino acid transporter repertoire. Furthermore, I highlight our approach of combining mechanistic insights from whole-animal Drosophila studies, with human cancer database analysis and human in vitro data to rationally target the nutrient vulnerabilities of tumourigenesis. Overall, this uncovers a novel concept and mechanism by which tumours exploit extracellular nutrients in response to systemic muscle wasting. This work therefore represents a new layer of tumour-host metabolic crosstalk which adds to our ever-growing appreciation of the intricacies of tumour-host interaction.