Host autophagy mediates organ wasting and nutrient mobilization for tumor growth

Abstract

During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed Xray tomography and metabolic profiling reveal that Ras V12 ; scrib À/À tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

RasV12; scrib−/− Tumors: A Cooperative Oncogenesis Model Fueled by Tumor/Host Interactions

“…The hyperglycemia and amino acid elevation in the hemolymph appear before the onset of alterations in feeding. This observation suggests that nutrient mobilization from wasted organs in the Ras V12 ; scrib −/− tumor-bearing larvae is mainly attributed to a long-range action of the tumor rather than starvation [115,137]. Collectively, this cohort of alterations of the organ structure and the systemic metabolism defines a wasting phenotype that is also observed in cancer patients who suffer from cachexia, establishing Drosophila as a relevant model to investigate the cachexia-associated mechanism (reviewed in [139]).…”

“…Autophagy is a process by which cells can degrade macromolecular components in the lysosome to recycle building blocks in nucleotides, sugars, amino acids, and fatty acids for anabolic or energetic demands. When autophagy is inhibited in the microenvironment, it strongly reduces tumor growth and malignancy in vivo [54,115]. Downregulation of an amino acid transporter Slimfast (Slif) limits the growth of a related cooperative model, Ras V12 ; dlg −/− [54], suggesting that these tumors are highly dependent on nutrients from their environment.…”

“…Ras V12 ; scrib −/− tumor-bearing larvae suffer weight loss, impaired motility and decreased feeding over time [115,137]. The energy-storing organs, such as the muscle and the fat body in the larva, progressively deteriorate over time so that many muscles shrink or rupture, and adhesion of fat body cells decreases and attains a "pearl-like" phenotype during the late stages of tumorigenesis [115,126,137]. The reduction of energy storage accompanies structural defects in these organs.…”

“…For instance, glycogen storage is significantly reduced in the muscle and the fat body and accompanied by mitochondrial defects. In contrast, lipid storage as triacylglycerides in the fat body seems to be stable, as lipidfree cytoplasm shrinks and lipid droplet aggregation ensues [115,126]. These changes correlate with an increase of amino acid and sugar levels in the larval hemolymph (insect blood), a phenotype shared with a high-sugar diet-induced Ras V12 , csk −/− larval tumor model [115,[135][136][137][138].…”

“…In contrast, lipid storage as triacylglycerides in the fat body seems to be stable, as lipidfree cytoplasm shrinks and lipid droplet aggregation ensues [115,126]. These changes correlate with an increase of amino acid and sugar levels in the larval hemolymph (insect blood), a phenotype shared with a high-sugar diet-induced Ras V12 , csk −/− larval tumor model [115,[135][136][137][138]. The hyperglycemia and amino acid elevation in the hemolymph appear before the onset of alterations in feeding.…”