HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Is the lactate value predictive of the return of spontaneous circulation during CPR in nontraumatic OHCA?

AIM OF THE STUDY: Cardiac arrest is a major public health issue, in which emergency medical services (EMS) initiating or continuing resuscitation in about 50% to 60% of cases. The aim of this study was to determine whether blood lactate levels and their course during cardiopulmonary resuscitation are prognostic indicators of the return of spontaneous cardiac activity (ROSC) in non-traumatic out-of-hospital cardiac arrest (OHCA). METHODS: This was a prospective, interventional, multi-center study between 2017 and 2020. Patients above the age of 18 years (>50 years for women) who had non-traumatic OHCA and did not achieve ROSC before the arrival of the EMS, and for whom the medical team decided to initiate or continue cardiopulmonary resuscitation have been included. The primary endpoint was the return of spontaneous cardiac activity during out-of-hospital cardiopulmonary resuscitation, and secondary endpoint was survival at day 28. The lactate was initially measured simultaneously on a venous and capillary sample and then in capillary samples throughout the CPR, using POC device. RESULTS: A total 60 patients were included. Median age was 71 [IQR: 62-84] and 21.3% were female. Among them, 25% underwent ROSC in out-of-hospital setting, and 13,3% were alive at D-28. The median venous lactate value in all patients at T0 (time at which the EMS set up the peripheral venous line) was 6.2 mmol/L [IQR: 4.6-8.1], with no difference between patients with or without ROSC: 6.4 mmol/L [IQR:4.7-7.9] for patients with ROSC and 6.2 mmol/L [IQR: 4.7-8] for patients without ROSC (p = 0.87). The variables independently associated with ROSC were initial EtCo2 value (aOR = 1.12; 95% CI 1.01-1.25); the initial shockable rhythm (aOR = 10.2; 95% CI 1.18-88.2); and the pre-ROSC adrenaline dose (aOR = 0.54; 95% CI 0.35-0.82). CONCLUSION: In this prospective multi-center study, there was no independent association between lactate values during cardiopulmonary resuscitation and ROSC in non-traumatic OHCA. However, the post-ROSC pre-hospital kinetics of lactate (i.e., during the first 30 min) seem to be associated with survival.

The mitochondrial NADH shuttle system is a targetable vulnerability for Group 3 medulloblastoma in a hypoxic microenvironment.

Medulloblastoma is a cancerous brain tumor that affects mostly children. Among the four groups defined by molecular characteristics, Group 3, the least well characterized, is also the least favorable, with a survival rate of 50%. Current treatments, based on surgery, radiotherapy, and chemotherapy, are not adequate and the lack of understanding of the different molecular features of Group 3 tumor cells makes the development of effective therapies challenging. In this study, the problem of medulloblastoma is approached from a metabolic standpoint in a low oxygen microenvironment. We establish that Group 3 cells use both the mitochondrial glycerol-3 phosphate (G3PS) and malate-aspartate shuttles (MAS) to produce NADH. Small molecules that target G3PS and MAS show a greater ability to decrease cell proliferation and induce apoptosis specifically of Group 3 cells. In addition, as Group 3 cells show improved respiration in hypoxia, the use of Phenformin, a mitochondrial complex 1 inhibitor, alone or in combination, induced significant cell death. Furthermore, inhibition of the cytosolic NAD+ recycling enzyme lactate dehydrogenase A (LDHA), enhanced the effects of the NADH shuttle inhibitors. In a 3D model using Group 3 human cerebellar organoids, tumor cells also underwent apoptosis upon treatment with NADH shuttle inhibitors. Our study demonstrates metabolic heterogeneity depending on oxygen concentrations and provides potential therapeutic solutions for patients in Group 3 whose tumors are the most aggressive.

HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.