FSMP-14. METABOLIC SYMBIOSIS IN GLIOBLASTOMA: LACTATE DEHYDROGENASES TAKE THE LEAD

Abstract

Glioblastoma (GBM) is a common and devastating brain tumor, associated with a low median survival, despite standard therapeutic management. Among its major features, GBMs are highly angiogenic, infiltrative, and exhibit paradoxically an elevated glycolysis. Most of differentiated cells convert glucose into pyruvate that enters into the Krebs cycle to maximize energy production in the presence of oxygen. For cancer cells, glucose uptake and catabolism are increased regardless of oxygen level. However, tumor cell energy needs are important, mainly for rapid growth, which require a much faster production flow. Lactate dehydrogenase (LDH) are involved at this step. LDHA converts pyruvate into lactate, and generates NAD+ to maintain glycolysis. Thus, lactate is exported into the extracellular compartment inducing an acidification of the microenvironment. Moreover, LDHB, another LDH isoform, metabolizes lactate into pyruvate for generating energy in mitochondria. LDHB is generally expressed in oligodendrocytes or neurons, but also in GBM cells. Though LDHA has already been studied in many cancers including GBM, the simultaneous role of LDH enzymes have not yet been investigated in GBM development. Our results showed that hypoxia significantly increased LDHA expression and lactate production, but no changes were observed for LDHB. In presence of lactate, cell invasion was significantly increased. In vitro results showed that, under hypoxic condition, double sgLDHA/B cell growth and invasion was dramatically decreased in comparison to control cells, mainly caused by an increase in apoptosis. In vivo experiments showed that double impairment of LDHA and B significantly reduced tumor growth and cell invasion, and induces a massive increase in mouse survival. Considered for a long time as a metabolic waste, lactate is shown here to play a critical role in the tumor niche. This study highlighted GBM adaptability through the LDH isoforms and their involvement in GBM development.