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.