Who regulates the key regulator? The Superti-Furga laboratory at CeMM reports online in the journal Science about a newly discovered mechanism by which RAS proteins, central to cancer signaling, are regulated in their activity and localization.
Of the more than 23,000 genes in the human genome, only a handful assume a very central role in signal transduction and growth regulation. Of these, the three genes encoding RAS proteins are particularly important, as they are found mutated in over 25% of human cancers. The processes around the RAS gene products are also involved in a variety of rare human developmental disorders called the RASopathies. RAS proteins are absolutely central regulators of growth and oncogenesis and, in turn, every regulator of RAS is poised to be fundamentally important for cancer and a broad variety of human diseases.
Driven by the interest in identifying underlying genetic determinants of drug response in a specific type of cancer of the hematopoietic system, CeMM now reports on the mechanistic link between the LZTR1 gene, previously associated with a variety of rare disorders and rare cancers, and RAS. These findings provide a new key regulator of a pathway that is one of the best studied signaling pathways in biology. As such, it represents a major advancement. The study not only sheds new light and details on the regulation of a central growth-promoting protein, but also offers a molecular explanation for an unusually large number of pathological conditions, ranging from different types of brain and pediatric cancers to developmental pathologies like Noonan syndrome.
The research team found that the protein called LZTR1, in concert with its copartner cullin 3, regulates RAS by attaching to it a small molecular tag, called ubiquitin. The modified RAS proteins demonstrate altered localization within the cell and reduced abundance. Mutational defects or inactivation of LZTR1 lead to an increase of RAS dependent pathways causing dysregulation of growth and differentiation. LZTR1 can therefore be considered a breaker of RAS action.
Johannes W. Bigenzahn, Giovanna M. Collu, Felix Kartnig, Melanie Pieraks, Gregory I. Vladimer, Leonhard X. Heinz, Vitaly Sedlyarov, Fiorella Schischlik, Astrid Fauster, Manuele Rebsamen, Katja Parapatics, Vincent A. Blomen, André C. Müller, Georg E. Winter, Robert Kralovics, Thijn R. Brummelkamp, Marek Mlodzik, Giulio Superti-Furga. LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018 November 15. doi:10.1126/science.aap8210.
The study was supported by the following funding agencies and grants: Austrian Academy of Sciences, European Research Council (ERC) grants (i-FIVE 250179 and Game of Gates 695214) and starting grant (ERC-2012-StG 309634), Austrian Science Fund grant (FWF SFB F4711 and F4702), EMBO (ALTF 1346-2011, 1543-2012), NIH grants R01 EY013256 and GM102811, Cancer Genomics Center (CGC.nl), KWF grant NKI 2015-7609.
We are happy to announce that during Summer/Autumn we had a successful search for new CeMM and LBI-RUD Adjunct Principal Investigators.
A warm WELCOME to:
Miriam Unterlass (CeMM) - Materials Chemistry, Technical University of Vienna
Nuno Maulide (CeMM) – Organic Chemistry, University of Vienna
Andreas Villunger (CeMM/LBI-RUD) – Division of Developmental Immunology, Medical University of Innsbruck
Thomas Reiberger (LBI-RUD/CeMM) – Division of Gastroenterology and Hepatology, Medical University of Vienna
Georg Stary (LBI-RUD/CeMM) – Department of Dermatology, Medical University of Vienna
We were looking for MD and/or PhD scientists either at their first independent appointment or already at the consolidation/advanced stage to apply their expertise close to a clinical setting. Particularly with those departments and in those areas we did not yet entertain extensive collaborations or have already extensive expertise. We offer a collaboration/affiliation contract for initially 5 years with the institution(s) mentioned in brackets, including a PhD student position, consumables and facility service funds. Adjunct PIs will be active members of our Faculty and be fully committed to participate in our Friday Seminars and the PhD Program.
CeMM and LBI-RUD are grateful for all applications and the strong interest in working with us. It was a very difficult task for the hiring committee to compare the great diversity of applications, research areas, and candidates in the different stages of their career. We are already working on ideas to further broaden its network and to offer additional ways of collaboration.
The adult lung consists of different, highly specialized cell types that are protected by a variety of immune cells. Using advanced single cell sequencing methods, researchers of the Weizmann Institute of Science in Israel, the CeMM and the Medical University in Vienna discovered a hitherto unknown, fundamental role of basophils in the development of macrophages in the lung. The study, published in Cell, could open new clinical strategies to fight lung diseases.
Lungs are vital organs required for the uptake of oxygen in exchange for carbon dioxide. However, the enormous complexity of the respiratory organ is often underestimated and deserves a closer look: A broad range of specialized cells work closely together to ensure the proper functioning of the lung and provide the vital gas exchange. The development and maturation of this complex organ during the embryonal stages and after birth was largely unknown.
In the latest issue of Cell (DOI: 10.1016/j.cell.2018.09.009), scientists from Israel and Austria made an important contribution to the understanding of the pulmonary immune-development using a combination of high throughput single-cell RNA sequencing, functional assays and cutting-edge microscopy methods. The research group of Ido Amit from the Weizmann Institute of Science, together with the teams of Sylvia Knapp at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Department of Medicine I of the Medical University Vienna and Tibor Harkany at the Center for Brain Research of the Medical University of Vienna could establish the first comprehensive map of lung cell types and their inter-lineage crosstalk during development.
An unexpected finding: basophils, immune cells that were hitherto held responsible for allergic reactions, reside in lungs where they develop into a special subtype that produces crucial growth factors and cytokines. These cells are different from previously described basophils that circulate in the blood, and their role in development and homeostasis, specifically in the lungs, was never reported before. Basophils broadly interact with other cell types of the lung, especially macrophages. Molecular signals, emitted by basophils, assist in the maturation of macrophages into their lung-specific phenotype, the so called alveolar macrophage. These unique signals and their impact on macrophages suggest they may play a role in lung diseases and might therefore expose and potential target for novel immunotherapies.
Merav Cohen, Amir Giladi, Anna-Dorothea Gorki, Dikla Gelbard Solodkin, Mor Zada, Anastasiya Hladik, Andras Miklosi, Tomer-Meir Salame, Keren Bahar Halpern, Eyal David, Shalev Itzkovitz, Tibor Harkany, Sylvia Knapp, Ido Amit. Lung single cell signaling interaction map reveals basophil role in macrophage imprinting. Cell October 11, 2018. DOI: 10.1016/j.cell.2018.09.009
The study was funded by the Chan Zuckerberg Initiative (CZI), a HHMI International Scholar award, the European Research Council (ERC), a MRA Established Investigator Award, the Israel Science Foundation, a Helen and Martin Kimmel award for innovative investigation, the Israeli government, Ministry of Science and Technology, the Austrian Science Fund (FWF) and the European Molecular Biology Organisation (EMBO).
We are happy and proud to announce a new piece of art located in the small seminar room at CeMM:
Stiegenhaus, 11 Square Albin Cachot, 75013 Paris-13E / RC01-BDJ 2018
Balsa wood, lacquer, multi-part
approx. 270 x 520 x 32 cm
The artwork is a generous gift from our befriended artist Klaus Pamminger who has already contributed a piece of art to the CeMM Brain Lounge. Until Summer 2018 the wall sculpture was part of the exhibition COLLAGE at the Fotogalerie Wien. The sculpture “Stiegenhaus” shows construction lines that Klaus Pamminger took from the film Belle de Jour (1967) derived from the staircase that Séverine Sérizy (Catherine Deneuve) climbs in order to leave her old bourgeois life behind. The concrete haptic perception and play of colors of the wall sculpture correlates with the audible click-clack of the heels of Séverine’s shoes. The complementary video VENEZ!/Come in! is available at vimeo.com/288200649.
Klaus Pamminger is a recognized Austrian artist with numerous international exhibitions as well as presentations at Film Festivals and Art Fairs. He is known for media set pieces that inscribe themselves into architecture, image fragments from cinema films that the artist collages in photographs of his living space. The artwork was inauguration with a small celebration with the artist and invited guests at CeMM on October 4, 2018.
Creativity and free-mindedness are among the key factors critical to innovative science at CeMM. Our laboratories and offices are designed to be full of light with a lot of open space for interactions, and our partnership and dialogue with artists helped to enhance the building with yet more areas of inspiration and to foster out-of-the-box thinking. The Art Façade of the CeMM building, the Brain Lounge and the Time Capsule are already highly appreciated and integral parts of CeMM’s daily life and research activities. The new wall sculpture by Klaus Pamminger in our seminar room is an additional proof of the strong and valuable relationship between art and science at CeMM. Thank you!
Art&Science at CeMM https://cemm.at/artssociety/
To start the academic year with a community experience CeMM had its yearly Outing on Friday, October 5, 2018. This year´s thematic focus was on traffic and public transport, and built on our previous SMART lecture held by architect and urban design consultant Jan Gehl on “Livable cities for the 21st century”.
We were very glad for the opportunity to visit the light rail manufacturing plant of Siemens Mobility GmbH in the 11th district of Vienna which is usually not open to visitors. After a short presentation and introduction we had guided tours through the production halls learning more about the impressive logistics of a successful global company and the building process of railway vehicles for safe, cost-effective and environment-friendly passenger and freight transport.
We had a very nice lunch at the “Kantine in der Brotfabrik Wien", where experienced professionals run a social business and created jobs for people with less job opportunities.
And the afternoon was dedicated to a voluntary photo and group challenge. Again, with the overall topic traffic and public transportation. A lot of creative, artistic, profound, interesting and funny photos have been taken by our CeMM members in six different categories while walking and exploring the city. The winning pictures will be released through our social media channels soon. For those who participated in the afternoon program, the day ended with Vienna sausages and drinks at Bitzinger Wurst Stand at Albertinaplatz.
We thank all companies and our PR and Event Manager Eva Schweng and the Admin Team for making the outing an enjoyable and interesting event.
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.
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
The study was funded by the Austrian Science Fund, the European Union, the Austrian Academy of Sciences, and the European Research Council.
Thank you for the interest and applications! We will contact the candidates asap. CeMM and LBI-RUD plan to invite several candidates to a hearing, which will take place in the last week of September 2018.
Adjunct Principal Investigator Positions at LBI-RUD and CeMM, Vienna
Starting or consolidated level to begin in 2018/2019
CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences and LBI-RUD, the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases have identical principles of excellence, competitiveness, internationality as well as mentoring and training, and both operate in a unique mode of super-cooperation, connecting biology with medicine, experiments with computation, discovery with translation, and science with society. We are partner institutes and located in the very same research building in the middle of the Vienna medical campus. Both have a partnership with the Medical University of Vienna and several faculty members have dual affiliations.
To complement and strengthen the current Faculty, CeMM and LBI-RUD are offering Adjunct Principal Investigator positions to highly professional individuals who work on an exciting problem of molecular medicine, preferably but not exclusively pertaining to Rare and Undiagnosed Diseases, Molecular Pharmacology, Immunity, Infection Biology, Inflammation, Neurologic Diseases, Hematopoiesis, Hematological Malignancies, Genome Integrity, Blood, Vascular Disorders or Metabolic Disorders.
Whom we are looking for:
We are looking for MD and/or PhD scientists either at their first independent appointment or already at the consolidation stage to apply their expertise close to a clinical setting in a stimulating research environment. Required are scientific quality and originality, a track record of achievements as well as a collaborative and interdisciplinary mindset.
What we offer:
We offer a collaboration/affiliation contract for initially 5 years including a PhD student position, and some consumables and facility service funds. The unique opportunity to become part of the CeMM/LBI-RUD Faculty. Benefit from lively scientific exchange, extend your network, collaborate and explore new possibilities – in science and beyond.
If you have the necessary drive and passion to make a difference, apply now for one of several positions of ADJUNCT PRINCIPAL INVESTIGATORS at LBI-RUD/CeMM.
NEW (!) Deadline for Applications: August 20, 2018
Due to several requests and the summer break, we decided for a one-off extension of the deadline.
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.
Laurène Pfajfer*, Nina K. Mair*, Raúl Jiménez-Heredia, Ferah Genel, Nesrin Gulez, Ömür Ardeniz, Birgit Hoeger, Sevgi Köstel Bal, MD, Christoph Madritsch, Artem Kalinichenko, Rico Chandra Ardy, Bengü Gerçeker, Javier Rey-Barroso, Hanna Ijspeert, Stuart G. Tangye, Ingrid Simonitsch-Klupp, Johannes B. Huppa, Mirjam van der Burg, Loïc Dupré*, and Kaan Boztug* (*equal contribution). Mutations affecting the actin regulator WD repeat–containing protein 1 lead to aberrant lymphoid immunity. Journal of Allergy and Clinical Immunology, 2018. DOI: 10.1016/j.jaci.2018.04.023
The study was funded by the Vienna Science and Technology Fund, the Austrian Science Fund, the French National Agency for Research, a ZonMW Vidi grant and grants from the National Health and Medical Research Council of Australia.
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.
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
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).
RESOLUTE (Research empowerment on solute carriers), a public-private research partnership supported by the Innovative Medicines Initiative (IMI) with 13 partners from academia and industry, announced the start of a 5-year research project on July 1, 2018. The goal of the project is to intensify worldwide research on solute carriers (SLCs), a relatively understudied group of proteins that control essential physiological functions, and potentially establish them as a novel target class for medicine research and development.