Dissecting Metabolism-Growth Crosstalk in Sex-Specific Brain Tumor Development

Objective

Rapid cell proliferation demands metabolic and developmental plasticity to cope with changing nutrient conditions, a trait vital for normal growth but often exploited in cancer. Yet, how metabolic enzymes interact with canonical growth regulators in a sex-specific manner, remains poorly understood. META-GROW aims to fill this gap by dissecting conserved mechanisms linking metabolism and growth regulation , with a unique focus on sex- and cell-type specificity. Using Drosophila as a genetically tractable, in vivo model, META-GROW builds on key results from the candidate showing that the metabolic enzyme Glycerol-3-phosphate dehydrogenase (Gpdh1) interacts with central nutrient-sensor Target of rapamycin (TOR) pathway to regulate brain growth. Strikingly, combined loss of Gpdh1 and TOR inhibition (by rapamycin) induces ectopic brain growth, despite Gpdh1 loss alone having no effect and TOR inhibition causing systemic growth restriction and developmental delay. Importantly, Gpdh1 mutants reveal sex-specific differences, aligning with growing evidence that sex shapes metabolism, tumor progression, and therapeutic responses. Although the human ortholog GPD1 shows both tumor-promoting and suppressive roles across cancer types, its mechanistic significance and sex-specificity, remain unknown. This limits our understanding of how metabolic enzymes interface with growth signaling to drive tissue-specific and sex-dependent tumorigenesis. By targeted genetic manipulation, live imaging, and omics-driven approach, META-GROW will: 1) find sex-specificity and cellular dynamics of ectopic brain growth in Gpdh1 mutants with inhibited TOR; 2) uncover molecular mechanisms/targets that regulate ectopic brain growth; and 3) reveal how Gpdh1 modulates tumorigenesis in a sex-specific manner. By revealing conserved metabolic vulnerabilities and sex-linked regulatory nodes, META-GROW offers insights of direct relevance to cancer biology and guide more effective, sex-informed therapies.