Glioblastoma is a brain cancer with devastating prognosis. A new collaborative study by scientists from CeMM, MedUni Vienna and the Austrian Brain Tumor Registry network demonstrates how epigenetic analysis of tumor samples collected in routine clinical practice could be used to better classify and treat the disease. The results were published in Nature Medicine.

Glioblastoma is an aggressive brain cancer with a high degree of molecular heterogeneity among the cancer cells. This results in evolutionary selection for those cells that can withstand drug treatment. In order to develop better therapies for glioblastoma, detailed knowledge about the molecular heterogeneity of the tumor cells will be crucial, given that this heterogeneity provides the substrate from which drug resistance evolves. 

Whether and how epigenetic regulation changes when a glioblastoma becomes therapy-resistant has been a largely unsolved question. To investigate the role of epigenetics in glioblastoma disease progression, the research group of CeMM PI Christoph Bock analyzed DNA methylation in more than 200 glioblastoma patients, focusing on the epigenetic changes that occur during glioblastoma disease progression. In close collaboration with scientists at the Medical University of Vienna and clinicians at eight hospitals throughout Austria, a study published in Nature Medicine (DOI: 10.1038/s41591-018-0156-x) identified epigenetic changes that accompany glioblastoma progression and predict patient survival.

This research builds on the Austrian Brain Tumor Registry, spearheaded by Adelheid Woehrer from the Institute of Neurology at the Medical University of Vienna, who is a senior and corresponding author of the study. Combining epigenetic data with brain imaging and digital pathology, the study established important links between glioblastoma at the level of molecules, cells and organs. These associations can be exploited for improving disease classification. Moreover, this study provides a rich resource for understanding the role of epigenetics in glioblastoma and a new toolset with broad relevance for personalized medicine. 

Publication:

Klughammer J*, Kiesel B*, Roetzer T, Fortelny N, Kuchler A, Nenning KH, Furtner J, Sheffield NC, Datlinger P, Peter N, Nowosielski M, Augustin M, Mischkulnig M, Ströbel T, Alpar D, Erguener B, Senekowitsch M, Moser P, Freyschlag CF, Kerschbaumer J, Thomé C, Grams AE, Stockhammer G, Kitzwoegerer M, Oberndorfer S, Marhold F, Weis S, Trenkler J, Buchroithner J, Pichler J, Haybaeck J, Krassnig S, Mahdy Ali K, von Campe G, Payer F, Sherif C, Preiser J, Hauser T, Winkler PA, Kleindienst W, Würtz F, Brandner-Kokalj T, Stultschnig M, Schweiger S, Dieckmann K, Preusser M, Langs G, Baumann B, Knosp E, Widhalm G, Marosi C, Hainfellner JA, Woehrer A#, Bock C# (*These authors contributed equally to this work; #These authors jointly directed this work). The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space. Nature Medicine, August 27, 2018. DOI: 10.1038/s41591-018-0156-x 

Funding:

The study was funded by the Austrian Science Fund, the European Union, the Austrian Academy of Sciences, and the European Research Council.

The rearrangement of the cell´s inner scaffold, the cytoskeleton, is a vital process for immune cells. In a new collaborative study, led by scientists from LBI-RUD/CeMM, a rare inherited disease revealed a hitherto unknown role of a cytoskeleton-regulating factor for the proper functioning of the adaptive immune system. The study was published in the Journal of Allergy and Clinical Immunology.

In order to move, a body needs a strong scaffold. This is not only true on a macroscopic level, where animals rely on skeletons to support their muscles. It is also true on a cellular level: the cytoskeleton composed of actin filaments is crucial for every active movement of a cell. By rearranging these filaments, cells can stretch and wander in every direction, squeeze into the smallest gaps or wrap themselves around an object. Those processes are particularly important for the cells of the immune system, which are the most motile cells of the human body in order to fight against infectious agents. Defects of the cytoskeleton thus can have detrimental effects on the immune response and thereby on the ability of the organism to control infections.

In their most recent study, scientists from the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) and CeMM in cooperation with the University of Toulouse III, and INSERM, found that a rare genetic defect, characterized by a malfunctioning of the immune system, affects the ability of lymphocytes – the most important cells of the adaptive immunity - to rearrange their actin cytoskeleton. The study, published in the Journal of Allergy and Clinical Immunology (DOI: 10.1016/j.jaci.2018.04.023) was conducted in collaboration with clinicians from Izmir and Ankara and specialists of lymphocyte biology from the University of Vienna and the University of Rotterdam.

The gene defect was found in six patients who presented with severe infections of the lung, skin and oral mucosa. Genetic analyses of their genomes revealed mutations in a gene for a protein called WDR1, an important factor for the turn-over of actin filaments and thereby the dynamic remodeling of the cytoskeleton. It was recently shown that the innate arm of the immune system is affected by WDR1 mutations - the impact on cells of the adaptive immunity, however, was hitherto unknown. Through a series of extensive analyses, the researchers found that WDR1 deficiency leads to aberrant T-cell activation and B-cell development. 

Patients with congenital diarrheal disorders, a group of rare inherited diseases with largely unknown mechanisms, suffer from severe to life-threatening diarrhea and nutrient malabsorption from birth. Using state-of-the-art genetic and molecular biology analysis methods involving the revolutionary gut organoid technology, researchers from the LBI-RUD and CeMM, together with the Medical University of Innsbruck and University Medical Center Utrecht identified the largest cohort of DGAT1-deficient patients to date. The scientists also unveiled the molecular mechanisms of the affected protein and discovered its crucial role in fat digestion. 

For our body to absorb fat from our diet, a series of complex biochemical reactions take place. First, the fat molecules consisting of a glycerol bound to three fatty acids (therefore also known as triglycerides) have to be digested by various enzymes into its components prior to being absorbed by cells of the small intestine, the enterocytes. Here, they are restored into triglycerides and packed into small particles which are released into the blood stream and transported into the rest of the body. If this process of dietary fat is disturbed, it can lead to devastating conditions.

This was the case with ten children from six families, all of whom suffered since birth from extreme diarrhea and/or vomiting. After a number of conventional therapies failed, the case of the young children was reported to the team of Kaan Boztug, Director of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) and Adjunct Principal Investigator of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. In collaboration with the Medical University of Innsbruck and University Medical Center Utrecht, the scientists performed DNA sequencing on the patients and identified mutations in the gene for a protein called diacylglycerol-acyltransferase 1 or DGAT1. The study was published in Gastroenterology (DOI:10.1053/j.gastro.2018.03.040).

DGAT1 is an enzyme crucial for the terminal step of triglyceride formation in enterocytes representing cells lining the intestinal tract. The scientists showed that the mutations resulted in a reduced or total lack of DGAT1 protein in cells of the patients. In an in vitro experiment, those cells were not able to metabolize lipids properly. Above that, the researchers were able to establish gut organoids - miniaturized and simplified structures with organ-like properties - out of patient-derived biopsies and recapitulated the effects of the genetic defect. Excitingly, repairing the function of DGAT1 in patient-derived fibroblast cells or inducing another enzyme called DGAT2  restored the lipid metabolism.

The study highlights the importance of genetic diagnosis of patients with early onset diseases as a crucial step for developing a proper care and therapy. At the same time, this work once again shows the general relevance of research on rare diseases, which in many cases not only helps affected patients, but also provides new insights into human biology.

Publication:

Jorik M van Rijn#, Rico Chandra Ardy#, Zarife Kuloğlu#, Bettina Härter#, Désirée Y. Van Haaften-Visser#, Hubert van der Doef, Marliek van Hoesel, Aydan Kansu, Anke H.M. van Vugt, Marini Thian, Freddy T.M. Kokke, Ana Krolo, Meryem Keçeli Başaran, Neslihan Gürcan Kaya, Aysel Ünlüsoy Aksu, Buket Dalgıç, Figen Ozcay, Zeren Baris, Renate Kain, Edwin C.A Stigter, Klaske D. Lichtenbelt, Maarten P.G. Massink, Karen J Duran, Joke B.G.M Verheij, Dorien Lugtenberg, Peter G.J Nikkels, Henricus G.F. Brouwer, Henkjan Verkade, Rene Scheenstra, Bart Spee, Edward E.S. Nieuwenhuis, Paul J. Coffer, Andreas R Janecke, Gijs van Haaften, Roderick H.J. Houwen, Thomas Müller*, Sabine Middendorp* and Kaan Boztug* (#shared first authors, *shared senior authors). Intestinal failure and aberrant lipid metabolism in patients with DGAT1 deficiency. Gastroenterology, July, 2018. DOI:10.1053/j.gastro.2018.03.040

Funding:

The study was funded by the Austrian Academy of Sciences, the OeNB Jubiläumsfonds, the Netherlands Organisation for Scientific Research and the European Research Council (ERC).

EU-LIFE, the alliance of 13 leading life science research institutes in Europe announced its reaction to the European Commission´s proposal for Horizon Europe, the next Framework Programme for Research and Innovation (FP9) that will run from 2021 to 2027. 

The key points are as follows: 

• EU-LIFE urges the European Parliament and the EU Council to push for a stronger Horizon Europe by raising its budget as recommended by several reports

• EU-LIFE encourages Horizon Europe to expand the extremely successful programmes it has initiated, namely the ERC grant system and Marie Skłodowska-Curie Actions, in addition to collaborative projects that address technological and environmental  challenges facing our society today. These actions attract and foster the best and brightest minds, and encourage ground-breaking research that will ensure Europe’s leadership in technological and biomedical innovation in the future. 

• EU-LIFE supports the statement released by 14 university organisations on calling for: increased total budget of Horizon Europe, a review of budget allocation, centre  the Programme’s pillars on the realisation of the European Research Area, better integration among research, innovation and education.

• Support for the announced ‘mission’ actions and a recommendation that researchers and innovators are involved in identifying and managing missions  

EU-LIFE’s full statement is available on: http://eu-life.eu/tags/publication

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Immune cells promoting inflammation play a crucial role in the development of atherosclerosis. Scientists at CeMM and the Medical University of Vienna in collaboration with the University of Cambridge showed that a survival factor for those cells has also anti-inflammatory functions and a protective role in atherosclerosis. The study, published in Circulation, provides valuable new insight for atherosclerosis research and suggests a hitherto unknown, inherited risk factor for atherosclerosis.

Atherosclerosis, the pathological narrowing of blood vessels, is the underlying cause for the majority of strokes and heart attacks, the major causes of mortality worldwide according to the WHO. For the development of atherosclerosis, a special type of white blood cells called B2 lymphocytes have been suggested to play a crucial role. For their survival, they need the molecule BAFF. It has been shown, that deletion or blockade of the BAFF receptors at the surface of B2 lymphocytes reduces the development of atherosclerosis in mice. Hence, a similar effect was expected when BAFF is directly targeted. 

With highly specific antibodies, BAFF can be bound and neutralized. Those antibodies where tested for their effects on the development of atherosclerosis in mice by scientists from CeMM and the Medical University of Vienna in collaboration with the University of Cambridge. The results were surprising: instead of reducing atherosclerotic lesion formation in the arteries of the tested mice, the antibody treatment lead to an increased plaque size. The findings were published in Circulation (DOI: 10.1161/CIRCULATIONAHA.117.032790).

The researchers - with Christoph Binder, CeMM PI and Professor for Atherosclerosis Research at the Medical University of Vienna as senior author - found BAFF to have anti-inflammatory properties, which has a positive effect on plaque size and atherosclerosis risk. The newly discovered mechanism is triggered by an alternative BAFF receptor (TACI) on the surface of macrophages, another type of immune cells. It was shown that these cells induce an anti-inflammatory process. This finding may provide important implications for atherosclerosis research and prevention: For example, mutations in the gene for TACI may confer an increased cardiovascular risk.

Publication

Dimitrios Tsiantoulas#, Andrew P. Sage#, Laura Göderle, Maria Ozsvar-Kozma, Deirdre Murphy, Florentina Porsch, Gerard Pasterkamp, Jörg Menche, Pascal Schneider, Ziad Mallat# and Christoph J. Binder#. (# equal contribution). BAFF Neutralization Aggravates Atherosclerosis. Circulation, June 5, 2018 . DOI: 10.1161/CIRCULATIONAHA.117.032790

Funding

The study was funded by the Austrian Science Fund FWF, the European Union, the British Heart Foundation and the European Research Council (ERC)

Fanconi anemia (FA), a rare, inherited disease, is caused by defective genes for DNA-repair in the cells of the patient leading to bone marrow failure, developmental abnormalities and increased cancer risk. Using genome-wide genetic approaches, researchers at CeMM systematically screened for the loss of an additional gene that could rescue the disease – and found it. The corresponding protein turned out to be a potential target that could be therapeutically exploited for FA. The study was published in Nature Communications.

Damaged DNA and its complex repair mechanisms is the research focus of the group of Joanna Loizou, Principal Investigator at CeMM, and finding new molecular targets to fight FA is one of their goals. In their latest study, published in Nature Communications (DOI 10.1038/s41467-018-04649-z), the researchers aimed to find additional genes that genetically interact with the diseased FA genes and are essential for the manifestation of the disease, and thereby, if destroyed, restore the ability of the cell to repair DNA crosslinks. The research project was performed in collaboration with scientists from the University of Cambridge, from the Leiden University Medical Center, the University of California, the University of Toronto and the group of Jörg Menche at CeMM.

The scientists, with former post doc of Loizou´s lab Georgia Velimezi and CeMM PhD student Lydia Garcia-Robinson as shared first authors, deployed a novel genetic screen to search for synthetic viable interactions, using a genome-wide loss-of-function approach that uses insertional mutagenesis achieved via a gene-trap approach, on special lines of FA-defective cells that only possess one copy of each gene. With this method, they scored a bulls eye: the researchers found an enzyme that removes ubiquitin, an important regulator of protein activity and half live, to be synthetic viable for FA gene deficiencies. 

When the enzyme, called USP48, was artificially destroyed by CRISPR/Cas9, the FA-deficient cells were less sensitive to DNA-damaging compounds and showed an increased clearance of DNA damage. With further molecular analysis of the underlying processes, the researchers were able to show that the inactivation of USP48 in FA-deficient cells even restored a nearly error free repair of the damaged DNA. 

Publication

Georgia Velimezi#, Lydia Robinson-Garcia#, Francisco Muñoz-Martínez, Wouter W. Wiegant, Joana Ferreira da Silva, Michel Owusu, Martin Moder, Marc Wiedner, Sara Brin Rosenthal, Kathleen M. Fisch, Jason Moffat, Jörg Menche, Haico Van Attikum, Stephen P. Jackson and Joanna I. Loizou. (#Co-first Author). Map of synthetic rescue interactions for the Fanconi anemia DNA repair 4 pathway identifies USP48. Nature Communications, June 11, 2018. DOI: 10.1038/s41467-018-04649-z.

Funding

The study was funded by the European Molecular Biology Organization (EMBO), the Austrian Science Fund (FWF), the European Commission, the European Research Council (ERC), the National Institutes of Health (NIH), Cancer Research UK, the Wellcome Trust and the Boehringer Ingelheim Fund (BIF).

Acute Myeloid Leukemia (AML) is an aggressive form of blood cancer that frequently develops in children. The diseased cells often carry mutated forms of a specific gene, which is known to function within large protein networks. Researchers at CeMM and LBI-CR identified a protein of this network crucial for the survival of the cancer cells – a novel potential approach for targeted therapies. The study was published in Nature Communications.

AML is not a single disease. It is a group of leukemias that develop in the bone marrow from progenitors of specialized blood cells, the so-called myeloid cells. Rapidly growing and dividing, these aberrant cells crowd the bone marrow and bloodstream, which can be fatal within weeks or months if the disease is left untreated. Myeloid cells of various types and stages can become cancerous and cause AML, which makes the condition very heterogeneous and difficult to treat. Thus, finding drug targets that affect as many forms of AML as possible is a prime goal for researchers.

The research groups of Florian Grebien from the Ludwig Boltzmann Institute for Cancer Research, Giulio Superti-Furga, Scientific Director of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and Johannes Zuber, from the Institute of Molecular Pathology, tackled that question in their latest study. They were able to identify common, conserved molecular mechanisms that drive oncogenesis in the context of the large number of different MLL-fusion proteins by characterizing the protein-protein interaction networks of distantly related MLL fusion proteins. Their results were now published in Nature Communications (DOI:10.1038/s41467-018-04329-y)

The scientists identified the methyltransferase SETD2 as a critical effector of MLL-fusion proteins. Using genomic techniques including CRISPR/Cas9 genome editing, the researchers found that SETD2 loss caused induction of DNA-damage and ultimately cell death in the cancer cells. Moreover, SETD2 loss increased the lethal effect of Pinometostat, a drug that is currently in clinical development for treatment of leukemia patients with MLL fusions. These experiments might pave the way for a more effective therapy in the future using a combination of compounds. 

Publication:

Anna Skucha, Jessica Ebner, Johannes Schmöllerl, Mareike Roth, Thomas Eder, Adrián César-Razquin, Alexey Stukalov, Sarah Vittori, Matthias Muhar, Bin Lu, Martin Aichinger, Julian Jude , André C. Müller, Balázs Győrffy, Christopher R. Vakoc, Peter Valent, Keiryn L. Bennett, Johannes Zuber*, Giulio Superti-Furga* and Florian Grebien* (*equal contribution). MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. Nature Communications, 2018. DOI:10.1038/s41467-018-04329-y

Funding:

The study was funded by the European Commission, the European Research Council (ERC), the Austrian Science Fund (FWF), the Austrian Research Promotion Agency (FFG), the National Institutes of Health (NIH), the National Research, Development and Innovation Office, Hungary, and Boehringer Ingelheim.