Host autophagy mediates organ wasting and nutrient mobilization for tumor growth. (26th July 2021)

• Record Type: Journal Article
• Authors: Khezri, Rojyar; Holland, Petter; Schoborg, Todd Andrew; Abramovich, Ifat; Takáts, Szabolcs; Dillard, Caroline; Jain, Ashish; O'Farrell, Fergal; Schultz, Sebastian Wolfgang; Hagopian, William M; Quintana, Eduardo Martin; Ng, Rachel; Katheder, Nadja Sandra; Rahman, Mohammed Mahidur; Teles Reis, José Gerardo; Brech, Andreas; Jasper, Heinrich; Rusan, Nasser M; Jahren, Anne Hope; Gottlieb, Eyal; Rusten, Tor Erik
• Is Part Of: EMBO journal. Volume 40:Number 18(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-26
• Subjects: autophagy -- cancer cachexia -- Drosophila -- muscle -- tumor -- wasting; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2020107336
• Languages: English
• ISSNs: 0261-4189

Abstract

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 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. Synopsis: Autophagy maintains mitochondrial health and nutrient recycling in tumor cells, and promotes the transfer of amino acids from microenvironmental to tumor cells, thereby sustaining tumor metabolism and growth. In this study, X‐ray tomography, metabolomics and carbon tracing reveal that autophagy‐mediated wasting of distal tissues provides amino acids and sugars that increase eye tumor biomass in Drosophila melanogaster . Ras V12, scrib −/− tumors induce organ wasting and cause release of amino acids and sugar into circulation. Systemic autophagy mediates muscle wasting and nutrient release. Tumor biomass increasingly derive from host tissues as wasting ensues. Abstract : X‐ray tomography, metabolomics and carbon tracing reveal that autophagy‐mediated wasting of distal tissues provides amino acids and sugars that increase eye tumor biomass in Drosophila melanogaster .