Decoding nutrient sensing and metabolic regulation in the Drosophila Hipk tumor model

Sustaining proliferative signals and deregulating cellular energetics are two hallmarks of cancer. However, how oncogenic signals respond to nutrients and coordinate with metabolic states remains poorly understood. Here, using Drosophila melanogaster as a genetic model organism, we establish an in vivo tumor model with elevation of oncogenic fly Homeodomain-interacting protein kinase (Hipk). This tumor model features cell hyperproliferation, tumor invasion, and cellular changes reminiscent of epithelial-to-mesenchymal transition, including induction of matrix metalloproteinases and loss of E-cadherin. The tumor phenotypes arise from the redundant and/or synergistic effects of more than one perturbed oncogenic signaling pathway caused by elevated Hipk, underlying the need for targeting multiple signaling molecules to reduce tumor growth. To search for simpler therapeutic strategies, we examine the metabolic requirements of Hipk tumor growth.We find that high sugar potentiates the tumorigenic potential of Hipk. Mechanistically, nutrient sensors O-GlcNAc transferase (OGT) in the hexosamine signaling pathway and salt-inducible kinase 2 (SIK2) in the insulin signaling pathway physically bind to Hipk and induce covalent post-translational modifications of Hipk, namely O-GlcNAcylation and phosphorylation, respectively. Both nutrient sensors are required for Hipk protein expression and synergize with Hipk to drive tumor progression. Our works demonstrate two modes of nutritional regulation of Hipk, which can accelerate Hipk tumor growth in nutrient-rich conditions like diabetes. We further characterize the metabolic profile of the Hipk tumor model. The tumor cells display the oncogene Myc-induced aerobic glycolysis, which in turn functions to perpetuate Myc accumulation post-transcriptionally, forming a positive feedback loop. Disruption of the loop abrogates Hipk tumor growth. Downstream of the loop, the tumor cells harbor an accumulation of highly fused, functional mitochondria. Targeted inhibition of a Pd subunit of the respiratory complex I blocks the tumor growth. Our works reveal that both aerobic glycolysis and active mitochondrial metabolism are required to promote Hipk tumor growth.Taken together, using the Drosophila Hipk tumor model, we functionally characterize the nutrient sensing and metabolic crosstalk with cell signaling, and reveal potential metabolic vulnerabilities that could be exploited in cancer treatment.