GLUT1

Scientists have discovered how glioblastoma evades the immune system by inducing pro-tumor macrophages via a glucose based epigenetic modification. The Wistar Institute assistant professor Filippo Veglia, Ph.D., and team, have discovered a key mechanism of how glioblastoma -- a serious and often fatal brain cancer -- suppresses the immune system so that the tumor can grow unimpeded by the body's defenses. The lab's discovery was published in the paper, "Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma," in the journal Immunity. "Our study shows that the cellular mechanisms of cancer's self-preservation, when sufficiently understood, can be used against the disease very effectively," said Dr. Veglia. "I look forward to future research on metabolism-driven mechanisms of immunosuppression in glioblastoma, and I'm hopeful for all that we will continue to learn about how to best understand and fight this cancer." Until now, it has been poorly understood how monocyte-derived macrophages and microglia create an immunosuppressive tumor microenvironment in glioblastoma. The Veglia lab investigated the cellular "how" of glioblastoma immunosuppression and identified that, as glioblastoma progressed, monocyte-derived macrophages came to outnumber microglia -- which indicated that monocyte-derived macrophages' eventuality to becoming the majority in the tumor microenvironment was advantageous to the cancer's goal of evading immune response. Indeed, monocyte-derived macrophages, but not microglia, blocked the activity of T cells (immune cells that destroy tumor cells), in preclinical models and patients. The team confirmed this finding when they assessed preclinical models of glioblastoma with artificially reduced numbers of monocyte-derived macrophages. And as the group expected, the models with fewer malicious macrophages in the tumor microenvironment showed improved outcomes relative to the standard glioblastoma models. Glioblastoma accounts for slightly more than half of all malignancies that originate in the brain, and the prognosis for those diagnosed with the cancer is quite poor: only 25% of patients who receive a glioblastoma diagnosis will survive beyond a year. Glioblastoma is inherently dangerous due to its location in the brain and its immunosuppressive tumor microenvironment, which renders glioblastoma resistant to promising immunotherapies. By programming certain immune cells like macrophages, (such as monocyte-derived macrophages and microglia), to work for -- rather than against -- the tumor, glioblastoma fosters a tumor microenvironment for itself that enables the cancer to grow aggressively while evading anticancer immune responses. Having confirmed the role of monocyte-derived macrophages, the Veglia lab then sought to understand just how the cancer-allied immune cells were working against the immune system. They sequenced the macrophages in question to see whether the cells had any aberrant gene expression patterns that could point to which gene(s) could be playing a role in immunosuppression, and they also investigated the metabolic patterns of macrophages to see whether the macrophages' nonstandard gene expression could be tied to metabolism. The team's twin gene expression & metabolic analysis led them to glucose metabolism. Through a series of tests, the Veglia lab was able to determine that monocyte-derived macrophages with enhanced glucose metabolism and expressing GLUT1, a major transporter for glucose (a key metabolic compound), blocked T cells' function by releasing interleukin-10 (IL-10). The team demonstrated that glioblastoma-perturbed glucose metabolism in these macrophages induced their immunosuppressive activity. The team discovered the key to macrophages' glucose-metabolism-driven immunosuppressive potency lies in a process called "histone lactylation." Histones are structural proteins in the genome that play a key role in which genes -- like IL-10 -- are expressed in which contexts. As rapidly glucose-metabolizing cells, monocyte-derived macrophages produce lactate, a by-product of glucose metabolism. And histones can become "lactylated" (which is when lactate becomes incorporated into histones) in such a way that the histones' organization further promotes the expression of IL-10 -- which is effectively produced by monocyte-derived macrophages to help cancer cells to grow. But how can the glucose-driven immunosuppressive activity of monocyte-derived macrophages be stopped? Dr. Veglia and his research team identified a possible solution: PERK, an enzyme they had identified as regulating glucose metabolism and GLUT1 expression in macrophages. In preclinical models of glioblastoma, targeting PERK impaired histone lactylation and immunosuppressive activity of macrophages, and in combination with immunotherapy blocked glioblastoma progression and induced long-lasting immunity that protected the brain from tumor re-growth -- a sign that targeting PERK-histone lactylation axis may be a viable strategy for fighting this deadly brain cancer. Note: The work detailed in this publication was initiated at The H. Lee Moffitt Cancer Center during Dr. Veglia's time there and continued at Wistar.

Aerobic glycolysis, the process by which cells transform glucose into lactate, is key for eye development in mammals, according to a new study. Aerobic glycolysis, the process by which cells transform glucose into lactate, is key for eye development in mammals, according to a new Northwestern Medicine study published in Nature Communications. While it has been well known that retinal cells use lactate during cell differentiation, the exact role that this process plays in early eye development was not previously understood. The findings further the field's understanding of the metabolic pathways underlying organ development, according to Guillermo Oliver, PhD, the Thomas D. Spies Professor of Lymphatic Metabolism, Director of the Feinberg Cardiovascular and Renal Research Institute Center for Vascular and Developmental Biology, and senior author of the study. "For a long time, my lab has been interested in developmental biology. In particular, to characterize the molecular and cellular steps regulating early eye morphogenesis," Oliver said. "For us, the question was: 'How do these remarkable and critical sensory organs we have in our face start to form?'" Nozomu Takata, PhD, a postdoctoral fellow in the Oliver lab and first author of the paper, initially approached this question by developing embryonic stem cell-derived eye organoids, which are organ-like tissues engineered in a petri dish. Intriguingly, he observed that early mouse eye progenitors display elevated glycolytic activity and production of lactate. After introducing a glycolysis inhibitor to the cultured organoids, normal optic vesicle development halted, according to the study, but adding back lactate allowed the organoids to resume normal eye morphogenesis, or development. Takata and his collaborators then compared those organoids to controls using genome-wide transcriptome and epigenetic analysis using RNA and ChIP sequencing. They found that inhibiting glycolysis and adding lactate to the organoids regulated the expression of certain critical and evolutionary conserved genes required for early eye development. To validate these findings, Takata deleted Glut1 and Ldha, genes known for regulating glucose transport and lactate production from developing retinas in mouse embryos. The deletion of these genes arrested normal glucose transport specifically in the eye-forming region, according to the study. "What we found was an ATP-independent role of the glycolytic pathway," Takata said. "Lactate, which is a metabolite known as a waste product before, is really doing something cool in eye morphogenesis. That really tells us that this metabolite is a key player in organ morphogenesis and in particular, eye morphogenesis. I see this discovery as having broader implications, as likely also being required in other organs and maybe in regeneration and disease as well." Following this discovery, Takata said he plans to continue to take advantage of traditional and emerging developmental biology's tools such as mouse genetics and stem cells-derived organoids to study the role of the glycolytic pathway and metabolism in the development of other organs. The findings could also be useful in better understanding the direct effect that metabolites could have in regulating gene expression during organ regeneration and tumor development, Oliver said. "Both regeneration and tumorigenesis involve developmental pathways that go awry in some occasions, or you need to reactivate," Oliver said. "For many developmental processes, you need very strict transcriptional regulation. A gene is on or off at certain times, and when that goes wrong, that could lead to developmental defects or promote tumorigenesis. Now that we know that there are specific metabolites responsible for normal or abnormal gene regulation, this can broaden our thinking on approaches to therapeutic treatments." Additional Feinberg faculty co-authors include Ali Shilatifard, PhD, the Robert Francis Furchgott Professor and chair of Biochemistry and Molecular Genetics and director of the Simpson Querrey Institute for Epigenetics, Alexander Misharin, MD, PhD, associate professor of Medicine in the Division of Pulmonary and Critical Care, Jason M. Miska, PhD, assistant professor of Neurological Surgery and Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care and of Biochemistry and Molecular Genetics. The study was supported by an Illumina Next Generation Sequencing award

Green light from HAS to facilitate reimbursement of METAglut1TM test in France Decision paves the way for adoption and reimbursement of the test in Europe and the U.S. PARIS--(BUSINESS WIRE)-- METAFORA biosystems, today announces that the Haute Autorité de Santé (HAS), the French Health Technology Agency, has issued a recommendation for insurance coverage of METAglut1TM, a test for the early diagnosis of De Vivo disease (or GLUT1 deficiency syndrome), a rare neurometabolic disorder. The HAS conducted a thorough evaluation of METAglut1TM, which included an assessment of its clinical performance and clinical utility. The evaluation concluded that METAglut1 is a valuable addition to the diagnostic arsenal for Glut1 DS, and was ascribed a high clinical added value. Vincent Petit, CEO of Metafora, said, “We are extremely proud to obtain HAS approval for METAglut1, a true milestone for the company and our partners, and not least for GLUT1 deficient patients. This rare neurometabolic disease is highly underdiagnosed, and we expect that METAglut1’s availability will increase awareness and help physicians to diagnose the disease earlier. We are grateful for the Forfait Innovation of the French Ministry of Health, which has allowed us to bring a multi-year prospective study to its successful conclusion. We look forward to making METAglut1 available to patients and clinicians in France and other large European countries, while we are actively exploring ways to launch the test in the U.S. as well.” Principal Investigator Prof. Fanny Mochel, Head of the Reference Centre for Adult Neurometabolic Diseases at AP-HP Pitié-Salpêtrière Hospital said, “METAglut1 quickly and accurately diagnoses GLUT1 deficiency syndrome. Its reimbursement will be of major benefit to physicians, pediatricians and neurologists, but especially to patients with this rare disease, as its early diagnosis is essential for targeted therapeutic management that can significantly improve the symptoms and daily lives of patients and their families.” About De Vivo disease & METAglut1TM – diagnose to cure De Vivo disease, or GLUT1 deficiency syndrome, is a rare and debilitating neurological disease. An estimated 30,000 people suffer from the GLUT1 deficiency syndrome in Europe and the USA, of which less than 2,000 are currently diagnosed. GLUT1-deficient patients suffer from an impaired glucose uptake by brain cells, leading to epileptic seizures, ataxia and often developmental delay. Uniquely, unlike for many genetic diseases, treatment is relatively straightforward, requiring a high-fat diet (known as a ketogenic diet), which significantly improves symptoms in patients. Early diagnosis is therefore of the essence. A multicenter validation study supported by the French Society of Neuropediatrics (SFNP) and the French Society for the Study of Innate Metabolic Diseases (SFEIM), was presented at the 3rd European GLUT1D Conference in 2021 and is accepted for a forthcoming publication in a leading scientific journal. It demonstrated that METAglut1 resulted in almost 100% specificity and a sensitivity of approximately 80%. METAglut1 identifies affected children and adults within 48 hours, unlike current diagnostic tests which rely on a lumbar puncture, an invasive procedure, and complex genetic analysis. METAglut1 is the result of a collaboration between METAFORA biosystems, the teams at Greater Paris University Hospitals (AP-HP), over 30 clinical trial sites, Cerba HealthCare, a clinical testing laboratory responsible for supporting the rollout of METAglut1 in France, and CNRS. METAglut1 is the first product to receive a recommendation through the Forfait Innovation program supported by the French Ministry of Solidarity and Health. The Forfait Innovation was critical in supporting a 30-month study in over 60 pediatric and adult neurology centers in France to demonstrate the efficacy of METAglut1 for the early detection of the GLUT1 deficiency syndrome. About METAFORA biosystems Metafora biosystems is a health-tech company based in Paris with 30 employees, developing a single-cell analysis platform. This platform allows to measure changes in single-cell metabolism, and determine “cell metabolic fitness” or lack thereof, which is a telltale sign of disease, especially in neurology, cancer and inflammatory diseases. METAglut1 is a first diagnostic test for the early diagnosis of De Vivo disease, a rare pediatric neurometabolic disorder. The company has forged key partnerships, notably with Sebia, a leading player in in vitro diagnostics, for the development of new diagnostic tests in oncology, and of a solution to increase the clinical efficacy of cell therapies and reduce manufacturing costs. Metafora has also developed METAflowTM, a cytometry data analysis software with unmatched robustness and a user-friendly interface that yields objective, reproducible, and actionable results from the increasingly large and unwieldy data sets generated by conventional, mass or spectral cytometry. A first research use only version will be launched by mid-2023, and developments are ongoing to turn METAflow into a clinical grade solution. Metafora has received grants to develop its technology platform from Bpifrance and funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 806038, and is laureate of the EIC Accelerator program from the European Commission. View source version on businesswire.com: Contacts For further information: Vincent Petit, CEO Phone: +33 6 76 71 61 14 Email: vincent.petit@metafora-biosystems.com Source: METAFORA biosystems View this news release online at: