Warburg Effect Metabolism Drives Neoplasia in a Drosophila Genetic Model of Epithelial Cancer
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- Warburg Effect Metabolism Drives Neoplasia in a Drosophila Genetic Model of Epithelial Cancer
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Cancers develop in a complex mutational landscape. Genetic models of tumor formation have been used to explore how combinations of mutations cooperate to promote tumor formation in vivo. Here, we identify lactate dehydrogenase (LDH), a key enzyme in Warburg effect metabolism, as a cooperating factor that is both necessary and sufficient for epidermal growth factor receptor (EGFR)-driven epithelial neoplasia and metastasis in a Drosophila model. LDH is upregulated during the transition from hyperplasia to neoplasia, and neoplasia is prevented by LDH depletion. Elevated LDH is sufficient to drive this transition. Notably, genetic alterations that increase glucose flux, or a high-sugar diet, are also sufficient to promote EGFR-driven neoplasia, and this depends on LDH activity. We provide evidence that increased LDHA expression promotes a transformed phenotype in a human primary breast cell culture model. Furthermore, analysis of publically available cancer data showed evidence of synergy between elevated EGFR and LDHA activity linked to poor clinical outcome in a number of human cancers. Altered metabolism has generally been assumed to be an enabling feature that accelerates cancer cell proliferation. Our findings provide evidence that sugar metabolism may have a more profound role in driving neoplasia than previously appreciated. Eichenlaub et al. examine gene expression changes during the transition from hyperplasia to neoplasia and identify lactate dehydrogenase as a key driver of neoplasia in a Drosophila EGFR model. Elevated sugar flux or a high-sugar diet also drive neoplasia. Synergy between EGFR and LDHA correlates with poor clinical outcome in some human cancers.
|Status||Udgivet - 2018|
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