Rusten, T. E. | bioRxiv Science

bioRxiv2020

Host autophagy mediates organ wasting and nutrient mobilization 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 recycling1. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids2-4. 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 RasV12; 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.

cell biology↗

bioRxiv2020

Natural abundance isotope ratios to differentiate sources of carbon used during tumor growth in vivo

BackgroundRadioactive or stable isotopic labeling of metabolites is a strategy that is routinely used to map the cellular fate of a selected labeled metabolite after it is added to cell culture or to the circulation of an animal. However, the transformation of the labeled metabolite by cellular metabolism within organs complicates the use of this experimental strategy to quantify and understand metabolite transfer between organs. These methods are also technically demanding, expensive and potentially toxic. To allow quantification of the bulk movement of metabolites between organs, we have developed a novel application of stable isotope ratio mass spectrometry (SIRMS). ResultsWe exploit natural differences in 13C/12C ratios of plant nutrients for a low-cost and non-toxic carbon labeling, allowing a measurement of bulk carbon transfer between organs in vivo. SIRMS measurements were found to be sufficiently sensitive to measure organs from individual Drosophila melanogaster larvae, giving robust measurements down to 2.5 {micro}g per sample. We apply the method to determine if carbon incorporated into a growing solid tumor is ultimately derived from food or host tissues. ConclusionMeasuring tumor growth in a D.melanogaster larvae tumor model reveals that these tumors derive a majority of carbon from host sources. We believe the low cost and non-toxic nature of this methodology gives it broad applicability to study carbon flows between organs also in other animals and for a range of other biological questions.

cancer biology↗