Abstract A04: Metabolic reprogramming of MYCN amplified neuroblastoma

Neuroblastoma (NB) is a highly malignant embryonic tumor of neural crest origin and accounts for 15% of all cancer deaths in children. Amplification of the MYCN oncogene, which occurs in ~25% of patients, is the most reliable marker of metastatic disease and predicts poor outcome. Recent findings show MYCN reprograms NB cell metabolism to promote glycolysis and shunting of glutamate into the TCA cycle, causing dependence on increased levels of TCA intermediates, such as a-KG and succinate. Allelic loss of the short arm of chromosome 1, (1p36) is associated with the vast majority of MYCN amplified NB, and a candidate tumor suppressor gene (TSG) in this region is succinate dehydrogenase subunit B,SDHB, which encodes a core component of the succinate dehydrogenase (SDH) complex, converting succinate to fumarate. We show that MYCN-amplified NB cells, with 1p deletion, have reduced SDHB protein levels and elevated succinate levels. Thus, we are now testing a model that the combined loss of SDH activity with MYCN amplification causes dramatic accumulation of cytosolic succinate, which in turn stabilizes HIF1α to accelerate NB pathogenesis in vivo. To test this model, we have generated mutations in zebrafish sdhb to determine if 1) it is normally required for sympathetic neuron differentiation and 2) cooperates with MYCN to accelerate zebrafish NB in vivo (Zhu et. al, Cancer Cell, 2012). As HIF1a is predicted to be upregulated in SDH-deficient cells, as well as MYCN-amplified ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Myc and Metabolism - Metabolomics: Poster Presentations - Proffered Abstracts Source Type: research