Lipid metabolism of hepatocyte-like cells supports intestinal tumor growth by promoting tracheogenesis

Tumors require metabolic adaptations to support their rapid growth, but how they influence lipid metabolism in distant tissues remains poorly understood. Here, we uncover a novel mechanism by which gut tumors in adult flies reprogram lipid metabolism in distal hepatocyte-like cells, known as oenocytes, to promote tracheal development and tumor growth. We show that tumors secrete a PDGF/VEGF-like factor, Pvf1, that activates the TORC1-Hnf4 signaling pathway in oenocytes. This activation enhances the production of specific lipids, including very long chain fatty acids and wax esters, that are required for tracheal growth surrounding the gut tumor. Importantly, reducing expression in oenocytes of either the transcription factor Hnf4, or the elongase mElo that generates very long chain fatty acid robustly extends lifespan, suppresses tumor growth, tracheogenesis, and associated organ wasting/cachexia-like phenotypes. Further, altering the expression level of oenocyte Hnf4 or mElo in control flies afects intestinal tracheogenesis. Lipoprotein-mediated lipid transport and altered oenocyte lipid metabolism drive the observed changes in tracheogenesis. Finally, we demonstrate that this regulatory pathway is conserved in mammals, as VEGF-A stimulates lipid metabolism gene expression in human hepatocytes, and lung tumor-bearing mice show increased hepatic expression of Hnf4 and the lipid elongation gene Elovl7. Our findings reveal a previously unrecognized tumor-host interaction where tumors non-autonomously reprogram distal lipid metabolism to support their growth. This study not only identifies a novel non-autonomous role of the TORC1-Hnf4 axis in lipid-mediated tumor progression but also highlights potential targets for therapeutic intervention in cancer-associated metabolic disorders.