Warburg Effect Metabolism Drives Neoplasia in a Drosophila Genetic Model of Epithelial Cancer

Abstract

Highlights d LDH upregulation is required for the transition from hyperplasia to neoplasia d LDH expression drives tumor formation in the context of EGFR overexpression d Increased sugar uptake drives tumor formation in the Drosophila EGFR model d Synergy between EGFR and LDHA correlates with poor outcome in human cancer

The hallmarks of cancer are also the hallmarks of wound healing

“…Research on this cancer hallmark began almost a century ago when Warburg first described how cancer cells tend to use glycolysis rather than oxidative phosphorylation to fuel their activities (110,111). Recent studies in Drosophila show how lactate dehydrogenase, a key enzyme in Warburg effect metabolism, is necessary and sufficient for the switch from hyperplasia to neoplasia in skin cancer models (112). Positron emission tomography (PET) scanning in the clinic takes advantage of this phenomenon because cancer cells primarily using glycolysis are much more demanding of glucose than are healthy cells primarily generating energy through oxidative phosphorylation, and so radioactively tagged glucose highlights cancer cells within tissues (113).…”

Characterization of endogenous fluorescence in nonsmall lung cancerous cells: A comparison with nonmalignant lung normal cells

“…Cancer metabolism discovered by Otto Warburg almost one century ago, which has been known as the “Warburg effect”, is now an innovative direction of cancer research . During ATP production, cancerous cells preferably uptake the glucose and produce a large amount of lactate even in the presence of ambient oxygen due to mitochondrial dysfunction . Substantial progress thus has been made toward the deeper understanding of mechanisms and the consequences associated with metabolic reprogramming in cancer.…”

Genome-wide RNAi screen for context-dependent tumor suppressors identified using in vivo models for neoplasia in Drosophila

“…Under these conditions the imaginal discs retain normal epithelial organization, but grow considerably larger than normal. However, in combination with additional genetic or environmental changes, the tissue can become neoplastic and form malignant tumors [8,9,22] [28].…”

“…In addition to finding genes linked to known growth control pathways, a number of novel connections to Yki and EGFR driven tissue growth have been identified, which merit further investigation in the Drosophila genetic model. Exploring the potential relevance of genes identified in this manner to human cancer will involve assessing the correlation of candidate gene expression with clinical outcome across a broad range of cancers (eg [28,48]), as a starting point to identify biomarkers as well as novel candidate drug targets.…”

“…Combining these with additional genetic alterations can lead to neoplastic transformation and eventually metastasis [8,9,21,22] [28]. Here, we report results of large-scale screens combining UAS-RNAi transgenes with EGFR or Yki expression to identify negative regulators of these growth regulatory networks that can lead to aggressive tumor formation in vivo.…”