Systemic muscle wasting and coordinated tumour response drive tumourigenesis

Abstract

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.

Drosophila larval models of invasive tumourigenesis for in vivo studies on tumour/peripheral host tissue interactions during cancer cachexia

“…Even though overexpression of impL2 RNAi in this setting caused strong reduction of impL2 in the tumour (Figure S4A), we did not observe suppression of skeletal muscle wasting (Figure S4B). A similar result was reported in a larval tumour model of diet-induced cancer cachexia [27].…”

“…Hyperplastic tumours can also be generated in Drosophila by hyperactivation of the Hippo pathway [24, 31]. As in human cancer patients, adult Drosophila tumour models has revealed heterogenous wasting phenotypes dependent on tumour genetics and location as well as dietary conditions [23, 24, 27]. Therefore, to identify some key features driving cachexia-like tissue wasting by tumours, we analysed the impact on muscle wasting of genetically distinct tumours in otherwise similar conditions.…”

“…Several adult Drosophila tumour models have been used to identify tumour-secreted factors contributing to peripheric tissue wasting [23, 24], making tumours refractory to the action of pro-wasting factors [25] and driving host anorexia [26]. A Drosophila larval model of high-sugar diet (HSD)-enhanced tumourigenesis identified important metabolically induced molecular changes within tumours driving muscle wasting [27]. While these studies have provided invaluable insight into tumour driven mechanisms of cancer cachexia, less is known about the molecular changes occurring within peripheric tissues and their functional role in tumour-driven host tissue wasting.…”

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

“…Detailed μ‐CT and volumetric calculations presented here demonstrate that muscle wasting occurs in response to Ras V12 ; scrib −/− , but that the fat body volume is retained with increased signs of steatosis. Muscle wasting was also reported to be induced by fibroblast growth factor secretion in a Ras V12 , Csk‐IR larval model while this paper was being revised (Newton et al , 2020). In both models, a concomitant increase in amino acid serum levels is observed raising the question of what is the mechanism for nutrient mobilization.…”

Proline metabolism and redox; maintaining a balance in health and disease

“…In normal conditions, proline and hydroxyproline are assimilated from the diet in the small intestine and about 60% will be released by enterocytes into the circulation. During disease, enhanced hydroxyproline levels are associated with bone tumours and hepatic fibrosis, whereas increased systemic proline levels mirror carcinogenesis, diabetes and cachexia tumor model, it was shown that cachexic muscles released increased proline through the upregulation of two potential proline transporters, SLC36A1 and SLC36A4 (Newton et al 2019). Interestingly, hyperprolinemia itself has also been shown to lead to metabolic consequences through amino acid toxicity and dysregulated β-cell function in INS1-E insulinoma cells and isolated mouse islets (Liu et al 2016).…”