Oxidative Metabolism Drives Immortalization of Neural Stem Cells during Tumorigenesis

Highlights

• Metabolic reprogramming is rate limiting for Drosophila brain tumor formation

• Lineage defects lead to mitochondrial fusion and enhanced oxidative phosphorylation

• Mitochondrial fusion increases oxidative phosphorylation and NAD⁺ production

• Excessive NAD⁺ formation triggers tumor cell immortalization

Summary

Metabolic reprogramming is a key feature of many cancers, but how and when it contributes to tumorigenesis remains unclear. Here we demonstrate that metabolic reprogramming induced by mitochondrial fusion can be rate-limiting for immortalization of tumor-initiating cells (TICs) and trigger their irreversible dedication to tumorigenesis. Using single-cell transcriptomics, we find that Drosophila brain tumors contain a rapidly dividing stem cell population defined by upregulation of oxidative phosphorylation (OxPhos). We combine targeted metabolomics and in vivo genetic screening to demonstrate that OxPhos is required for tumor cell immortalization but dispensable in neural stem cells (NSCs) giving rise to tumors. Employing an in vivo NADH/NAD⁺ sensor, we show that NSCs precisely increase OxPhos during immortalization. Blocking OxPhos or mitochondrial fusion stalls TICs in quiescence and prevents tumorigenesis through impaired NAD⁺ regeneration. Our work establishes a unique connection between cellular metabolism and immortalization of tumor-initiating cells.