Journal
EMBO JOURNAL
Volume 40, Issue 18, Pages -Publisher
WILEY
DOI: 10.15252/embj.2020107336
Keywords
autophagy; cancer cachexia; Drosophila; muscle; tumor; wasting
Categories
Funding
- Norwegian Research Council [262652, 276070]
- HSO [40041]
- Division of Intramural Research at the National Institutes of Health/National Heart, Lung, and Blood Institute [1ZIAHL006126, 1K22HL137902]
- Laura and Isaac Perlmutter Fund
- Simon Fougner Hartmann's fund
- Office of Science, Research Council of Norway through its Centers of Excellence funding scheme [223272]
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In addition to supporting tumor metabolism and growth, autophagy plays a critical role in mediating systemic organ wasting and nutrient mobilization for tumor growth. The study demonstrates that autophagy mediates muscle atrophy and weight loss, leading to the release of amino acids and sugars into circulation for tumor growth.
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 X-ray tomography and metabolic profiling reveal that Ras(V12); scrib(-/-) 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.
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