Abstract 4342: Crosstalk between initiating cells with different metabolism in a murine model of malignant glioma

Abstract

Abstract Background The metabolic preference of malignant glioma for glycolysis as an energy source is a potential therapeutic target. As a result of the cellular heterogeneity of these tumors, however, the relation between glycolytic preference, tumor formation, and tumor cell clonogenicity has remained unknown. To address this issue, we analyzed the metabolic profiles of isogenic glioma-initiating cells (GICs) in a mouse model. Methods GICs were established by overexpression of H-RasV12 in Ink4a/Arf-null neural stem cells. Subpopulations of these cells were obtained by single-cell cloning, and clones differing in extracellular acidification potential were assessed for metabolic characteristics by quantification of intra- and extracellular metabolites. Tumorigenicity was assessed by implantation of 100 cells of each subpopulation into the forebrain of wild-type mice. Tumors were examined for pathological features of glioma and expression of glycolytic enzymes. Results Malignant transformation of neural stem cells resulted in a shift in metabolism characterized by a significant increase in glucose uptake and lactic acid production. Clonal populations of GICs also manifested pronounced differences in their metabolic profiles. Certain GICs consumed more glucose and produced more lactate, while others had higher oxygen consumption. These differences were reflected in the levels of intracellular metabolites and they were paralleled by a differential expression of glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2. GIC clones with different metabolic profiles had the same level of tumorigenic ability and the tumors formed by all types of GICs displayed the histopathological features of glioblastoma. However, the differential expression of the glycolytic enzymes was also evident in the tumors formed by each of the clones. Implantation of a mix of GICs with different metabolic profiles showed that clones with higher glycolytic ability were the major component of the tumor mass and that they provided a scaffold for the less glycolytic clones, supporting their expansion. Conclusions The metabolic characteristics of glioma cells appear early during malignant transformation and persist until the late stages of tumor formation. Even isogenic clones may be heterogeneous in terms of metabolic features, however, and this heterogeneity may play a role in tumor cell proliferation and survival. Our results suggest that a more detailed understanding of the metabolic profile of malignant gliomas is imperative for their effective therapeutic targeting. Citation Format: Oltea Sampetrean, Isako Saga, Shunsuke Shibao, Jun Okubo, Satoru Osuka, Nobuyuki Onishi, Hideyuki Saya. Crosstalk between initiating cells with different metabolism in a murine model of malignant glioma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4342. doi:10.1158/1538-7445.AM2014-4342