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

Project description

Exploring sex- and cell-type-specific growth regulation

Despite advances in cancer metabolism and growth signalling, their interaction across sex and cell types remains unexplored. Funded by the Marie Skłodowska-Curie Actions programme, the META-GROW project will use Drosophila as an in vivo model to build on the key finding that combined glycerol-3-phosphate dehydrogenase (Gpdh1) mutation and target of rapamycin (TOR) inhibition induce ectopic brain growth that forms tumours, despite Gpdh1 loss alone having no effect and TOR inhibition alone causing systemic growth restriction. Using genetics, live imaging and omics, META-GROW will investigate sex-specific cellular dynamics of ectopic brain growth in Gpdh1-TOR loss condition; the mechanisms driving it; and how Gpdh1 modulates tumours. By revealing conserved metabolic vulnerabilities and sex-linked regulatory nodes, META-GROW will guide sex-informed cancer therapies.

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.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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(opens in new window) HORIZON-MSCA-2025-PF

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Coordinator

UNIVERSIDADE NOVA DE LISBOA
Net EU contribution

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€ 207 183,12
Address
CAMPUS DE CAMPOLIDE
1099-085 Lisboa
Portugal

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Activity type
Higher or Secondary Education Establishments
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Total cost

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