P1.03-003 The Warburg Effect: Persistence of Stem Cell Metabolism in Lung Cancer as Failure of Differentiation

Abstract

Two recent observations are relevant to explaining Warburg's observation the cancers constitutively utilize glycolysis in the presence of oxygen sufficient for oxidative phosphorylation. First, the metabolism of stem cells has been shown to be constitutive (‘aerobic’) glycolysis, with differentiation involving a transition to oxidative phosphorylation. Second, the degree of glucose uptake by a cancer has been associated with histologic differentiation. We hypothesized that the high levels of glucose uptake observed in poorly differentiated lung cancers may reflect persistence in cancers of the glycolytic metabolism of stem cells that fail to fully differentiate. Tumor glucose uptake was measured by FDG-PET in 859 patients with histologically diverse cancers including NSCLC. We used normal mixture modeling to explore SUV distributions and tested for association between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Using microarray data, we performed pathway and transcription factor analyses to compare tumors with high/low glucose uptake. Well-differentiated NSCLC had low FDG uptake, and moderately/poorly differentiated tumors higher uptake. The distribution of FDG-PET uptake was modal with a low peak at SUV 2-4 and a high peak at SUV 8-11. The cancers in the two peaks were clinically distinct in terms of the risk of nodal metastases and of death. Carbohydrate metabolism-related and pentose/nucleotide synthesis-related genes were elevated in the high SUV clusters, Krebs cycle/glutamine metabolism-related genes were elevated in the low SUV mode samples. Expression of Myc target genes was associated with SUV mode, but Nanog, Sox2, Oct4 and PRC2 where not. The biological basis for the Warburg effect is persistence of stem cell metabolism in lung cancers as a failure to transition from glycolysis-utilizing undifferentiated cells to oxidative phosphorylation-utilizing differentiated cells. Lung cancers cluster along the differentiation pathway into two groups. Our results have implications for determining prognosis, cancer screening and surveillance after resection.