Abstract LB-051: High LDHA expression predicts decreased survival in neuroblastoma

Abstract

Abstract Neuroblastoma (NB) is a common pediatric malignancy that often carries a poor prognosis. Aerobic glycolysis, i.e. the Warburg effect, is a hallmark of cancers, including NB. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate. It is considered a pivotal component of the LDH tetramer, which is central in the Warburg effect. LDHA is overexpressed in many cancers. Little is known about the role of LDHA in NB. We therefore determined the expression of LDHA mRNA and protein in 651 and 112 clinically annotated patient samples, respectively. We show that enhanced mRNA expression and predominant cytoplasmic protein expression of LDHA, as detected by immunohistochemistry, is markedly associated with increased tumor aggressiveness and decreased patient survival. Surprisingly, despite the proposed pivotal role of LDHA in the Warburg effect, LDHA was dispensable for aerobic glycolysis in NB cells. Complete depletion of LDHA by CRISPR/Cas9-mediated knock-out in several NB cell lines did not decrease glucose consumption and production of pyruvate and ATP. In accordance, LDH activity was maintained despite loss of LDHA, as LDHB and LDHC were still expressed, most likely compensating for the loss of LDHA. In line with LDHA being dispensable for aerobic glycolysis in NB cells, LDHA depletion did not decrease malignant characteristics of NB cells. Thus, clonogenic growth, migration and tumorigenicity remained unaffected. Extending these findings from manifest to developing NB, we show that in the TH-MYCN NB mouse model the development of NB from normal sympathetic ganglia is not associated with increased LDHA expression. Taken together, this work establishes LDHA as a novel predictive marker in NB and calls into question the pivotal role in aerobic glycolysis attributed to LDHA. Citation Format: Carmen Dorneburg, Lisa Christner, Thomas F. Barth, Wolfgang Mueller-Klieser, Matthias Fischer, Hero Barbara, Anneleen Beckers, Frank Speleman, Klaus-Michael Debatin, Christian Beltinger. High LDHA expression predicts decreased survival in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-051. doi:10.1158/1538-7445.AM2017-LB-051