Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use a Drosophila model of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animal Drosophila model provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.

SUMMARYCancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic pertubations remain incompletely understood. Here we use a Drosophila model of obesity-enhanced tumourigenesis to uncover a systemic host-tumour nutrient circuit that supports tumour growth. We demonstrate coordinate induction of systemic cachexia-like muscle wasting with tumour-autonomous SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. This coordinated induction of cachexia and SLC36-transporters pertains to human kidney cancer and associates with significantly worse survival outcomes. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Combining insights from whole-animal Drosophila models and human cancer database analysis provides a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of perturbed systemic metabolic network.