Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.

Glioblastoma (GB) are the most frequent brain cancers. Aggressive growth and limited treatment options induce a median survival of 12–15 months. In addition to highly proliferative and invasive properties, GB cells show cancer-associated metabolic characteristics such as increased aerobic glycolysis. Pyruvate dehydrogenase (PDH) is a key enzyme complex at the crossroads between lactic fermentation and oxidative pathways, finely regulated by PDH kinases (PDHKs). PDHKs are often overexpressed in cancer cells to facilitate high glycolytic flux. We hypothesized that targeting PDHKs, by disturbing cancer metabolic homeostasis, would alter GB progression and render cells vulnerable to additional cancer treatment. Using patient databases, distinct expression patterns of PDHK1 and PDHK2 in GB tissues were obvious. To disturb protumoral glycolysis, we modulated PDH activity through the genetic or pharmacological inhibition of PDHK in patient-derived stem-like spheroids. Striking effects of PDHKs inhibition using dichloroacetate were observed in vitro on cell morphology and metabolism, resulting in increased intracellular ROS levels and decreased proliferation and invasion. In vivo findings confirmed a reduction in tumor size and better survival of mice implanted with PDHK1 and PDHK2 knockout cells. Adding a radiotherapeutic protocol further resulted in a reduction in tumor size and improved mouse survival in our model.

Background: Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology. Aims: Our study aimed to demonstrate and characterize the variability in the expression of the rewarding effects of cocaine in the conditioned place preference (CPP) paradigm. Methods: A cocaine-CPP paradigm in male Sprague–Dawley rats with an extinction period of 12 days and reinstatement was conducted. A statistical model was developed to distinguish rats expressing or not a cocaine-induced place preference. Results: Two groups of rats were identified: rats that did express rewarding effects (CPP expression (CPPE), score >102 s) and rats that did not (no CPP expression (nCPPE), score between −85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, a whole-transcriptome ribonucleic acid-sequencing analysis was performed in the nucleus accumbens (NAc) 24 h after the CPP test. Four immediate early genes ( Fos , Egr2 , Nr4a1 , and Zbtb37 ) were differentially expressed in the NAc of CPPE rats after expression of CPP. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after expression of CPP. Conclusion: These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine’s rewarding effects.

Le glioblastome (GB) est le cancer cérébral le plus fréquent mais aussi le plus agressif chez l’adulte. Outre d’importantes capacités prolifératives et invasives, induisant un mauvais pronostic et un fort taux de rechute, les cellules de GB présentent également une forte plasticité métabolique. En effet, la cohabitation de cellules glycolytiques et oxydatives dans la tumeur participe à l’établissement d’une symbiose métabolique favorisant la survie et la progression des cellules malignes, ainsi que leur échappement aux traitements actuels. Nos travaux ont permis de mettre en évidence cette symbiose métabolique intra-tumorale, centrée sur des échanges de lactate entre la population de la tumeur centrale et la population invasive. La déstabilisation de ce métabolisme du lactate intra-tumoral, en bloquant l’action d’acteurs impliqués directement, comme les LDHs, ou indirectement, comme les PDHKs, a montré des résultats encourageants en altérant la progression du GB in vitro et in vivo.En clinique, la résection tumorale, lorsqu’elle est possible, est la première intervention thérapeutique chez le patient. Acte traumatique et invasif pour le patient, l’exérèse de la masse tumorale est également traumatique pour la tumeur elle-même puisqu’elle désorganise totalement la symbiose métabolique intra-tumorale. De manière systématique, les cellules invasives ayant échappé à la résection sont capables de basculer vers un phénotype prolifératif pour reformer une tumeur. En effet, le retrait de la masse tumorale, fortement productrice de lactate, entraine des fluctuations de la concentration de ce métabolite dans les cellules résiduelles post-résection. Nos récents résultats montrent que ces fluctuations semblent induire des adaptations métaboliques favorisant survie et prolifération. Conjointement aux protocoles cliniques actuels, le blocage thérapeutique de ces reprogrammations métaboliques pourrait être une approche adaptée pour prévenir les récidives tumorales du GB.