March 09, 2020
A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs
Researchers around first author Enrico Girardi of the Giulio Superti-Furga lab at CeMM have studied how Solute Carriers (SLCs), a large family of membrane transport proteins, influence the activity and potency of cytotoxic drugs. The results show that many cytotoxic compounds need at least one functioning solute carrier transporter to unfold their activity. "The use of a custom-made, SLC-focused library was instrumental in allowing us to screen a large number of compounds, revealing hundreds of SLC-drug associations and providing many novel insights into SLC biology and drug mechanisms", says Enrico Girardi, CeMM senior postdoctoral fellow and first author of the study. Giulio Superti-Furga, CeMM Scientific Director and last author of the study adds: "This study raises strong doubts that the generally accepted idea that most drugs can enter cells by simply diffusing through its membrane is correct and highlights the increasingly appreciated need to systematically studying the biological roles of solute carriers". The present study is the result of a cross-disciplinary collaboration with researchers from the University of Vienna Pharmacoinformatics Research Group of Gerhard Ecker as well as the group of Stefan Kubicek at CeMM.
Enrico Girardi, Adrián César-Razquin, Sabrina Lindinger, Konstantinos Papakostas, Justyna Konecka, Jennifer Hemmerich, Stefanie Kickinger, Felix Kartnig, Bettina Gürtl, Kristaps Klavins, Vitaly Sedlyarov, Alvaro Ingles-Prieto, Giuseppe Fiume, Anna Koren, Charles-Hugues Lardeau, Richard Kumaran Kandasamy, Stefan Kubicek, Gerhard F. Ecker & Giulio Superti-Furga
Girardi, E., César-Razquin, A., Lindinger, S. et al.
A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs.
Nat Chem Biol (2020). https://doi.org/10.1038/s41589-020-0483-3
The study was funded with support by the Austrian Academy of Sciences, the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No. 695214, awarded to Giulio Superti-Furga), the Austrian Science Fund (FWF I2192-B22 ERASE; FWF P29250-B30 VITRA) and by a Marie Sklodowska-Curie fellowship to Enrico Girardi (MSCA-IF-2014-661491). Research in the Kubicek laboratory is supported by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology, and Development, the Austrian Science Fund (FWF) F4701 and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-CoG-772437). The Pharmacoinformatics Research Group (Ecker lab) acknowledges funding provided by the Austrian Science Fund FWF AW012321 MolTag.
July 18, 2019
New insights into cellular response to oncolytic VSV infection
CeMM researchers from the laboratory of Giulio Superti-Furga, with Anna Moskovskich as first author of the study, have identified two transporters, SLC35A1 & SLC30A1, with opposite effects on the regulated cell death induced by the virus.
Special thanks to Enrico Girardi, Co-Supervisor of PhD Student Anna, and Gijs Versteeg (Universität Wien) and Michael Freissmuth (Medizinische Universität Wien) for critical feedback.
The transporters SLC35A1 and SLC30A1 play opposite roles in cell survival upon VSV virus infection.
Moskovskich A, Goldmann U, Kartnig F, Lindinger S, Konecka J, Fiume G, Girardi E, Superti-Furga G.
Sci Rep. 2019 Jul 18;9(1):10471. doi: 10.1038/s41598-019-46952-9.
The study was supported with competitive funds from the Austrian Science Fund, European Research Council and European Commission.
June 3-5, 2019
2nd RESOLUTE Consortium Meeting
RESOLUTE, an European Union IMI2 funded project with 13 partners, CeMM as academic coordinator and Pfizer as EFPIA leader, celebrated the 2nd RESOLUTE consortium meeting from June 3-5, 2019 in Krems an der Donau, near Vienna.
More than 65 participants coming from all over Europe and the US joined the meeting. This was a great chance to review the current status of the RESOLUTE project right before completing the first year of collaborations. This edition featured many young investigators presenting their progress in the generation of reagents, data and assays for solute carriers. Additionally, strategies were developed for tackling the challenges of the second year of RESOLUTE. Participants as well enjoyed the excellent weather and cultural amenities of the beautiful vineyards of the Wachau area.
Learn more about the RESOLUTE (Research Empowerment on Solute Carriers) Project: https://re-solute.eu/
November 15, 2018
New mechanism controlling the master cancer regulator uncovered
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.
July 03, 2018
RESOLUTE: 13 academic and industry partners join forces to unlock the solute carrier class of transporters for effective new therapies
more information: https://re-solute.eu
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.
For more information please visit the RESOLUTE website: https://re-solute.eu
June 13, 2018
How immune cells kill bacteria with acid
The first line of immune defense against invading pathogens like bacteria are macrophages, immune cells that engulf every foreign object that crosses their way and kill it with acid, in a process called phagocytosis. In their quest to systematically study proteins that transport chemicals across cellular membranes, researchers at CeMM characterized the critical role for transporter SLC4A7 in this process, providing valuable new insights for many pathologic conditions from inflammation to cancer. Their results were published in Cell Host & Microbe.
Among the many different kinds of immune cells that patrol the body, macrophages are the first when it comes to fight against a foreign threat. With their flexible and versatile surface, they engulf every microorganism or particle that could be harmful for the health of the organism, and enclose it in an intracellular membrane vesicle called phagosome. To eliminate the threat and break it down to its constituents, the interior of the phagosome needs to be effectively and progressively acidified. For this crucial part of phagocytosis, the macrophages must undergo multiple metabolic changes, which are not yet entirely understood.
The team of Giulio Superti-Furga, Scientific Director of CeMM, in collaboration with the laboratory of Nicolas Demaurex of the University of Geneva, discovered in their latest study that a membrane protein belonging to the family of “solute carriers” (SLCs) plays an essential role in phagocytosis and phagosome acidification. Their work was published in the journal Cell Host & Microbe (DOI 10.1016/j.chom.2018.04.013).
The researchers developed an essay with special cells in which they impaired the 391 human SLC genes individually using CRISPR/Cas9 gene editing technology. Strikingly, among all SLCs, SLC4A7, a sodium bicarbonate transporter, was the only one who turned out to be essential for macrophages to undergo phagocytosis and acidification. Cells with impaired SLC4A7 were unable to acidify their phagosomes and by consequence decreased their capacity to kill bacteria.
The results of this study do not only provide new fundamental insights into the molecular functioning of one of the most important cells of the immune system. As phagocytosis plays a significant role in various pathologic conditions from inflammation to cancer, these new insights are likely of relevance beyond the context of infectious diseases. The effort to understand the role of the different cellular transporters, supported by a grant of the European Research Council (ERC), has added a small new piece to the large and fascinating puzzle coupling trafficking of chemical matter to metabolism and cellular function.
Vitaly Sedlyarov, Ruth Eichner, Enrico Girardi, Patrick Essletzbichler, Ulrich Goldmann, Paula Nunes-Hasler, Ismet Srndic, Anna Moskovskich, Leonhard X. Heinz, Felix Kartnig, Johannes W. Bigenzahn, Manuele Rebsamen, Pavel Kovarik, Nicolas Demaurex, and Giulio Superti-Furga. The Bicarbonate Transporter SLC4A7 Plays a Key Role in Macrophage Phagosome Acidification. Cell Host & Microbe, 2018. DOI: 10.1016/j.chom.2018.04.013
The study was funded by the European Research Council (ERC), the Austrian Academy of Sciences, the Austrian Science Fund (FWF), the European Commission, and the European Molecular Biology Organization (EMBO).
May 18, 2018
A New Achilles’ Heel of Blood Cancer
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.
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
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.
April 24, 2017
Next-Generation Microscopy with Pharmacoscopy
A novel microscopy method, developed and patented by scientists from CeMM, allows unprecedented insights into the spatial organization and direct interactions of immune cells within blood and other liquid multi-lineage tissues. The assay, called Pharmacoscopy and published in Nature Chemical Biology, is able to determine the immunomodulatory properties of drugs within large libraries on immune cells in high resolution and high throughput.
The search for new drugs, small molecule or biologicals, that influence the immune system in a desired manner is challenging: immune signaling, often a combination of communication via soluble proteins and direct interaction by cell-cell contacts, is subtle and hard to track in all its nuances. So far, there has been a lack of fast and robust technology to measure the effect of a potential immunomodulatory drug in particular in a cell-cell contact dimension.
By combining state-of-the-art high-throughput fluorescent microscopy with single cell image analysis and novel analysis algorithms, Pharmacoscopy provides a powerful solution. Developed by a group of scientists at CeMM led by Director Giulio Superti-Furga and tested in collaboration with the Medical University of Vienna, Pharmacoscopy can quantify the overall spatial patterning and direct interactions of immune cells within blood with unprecedented speed and accuracy. The method was introduced in Nature Chemical Biology (DOI:10.1038/nchembio.2360).
Combined single cell resolution and fully automated platform control, Pharmacoscopy can test large drug libraries, as available in Stefan Kubicek’s PLACEBO (Platform Austria for Chemical Biology) laboratory, for compounds with immunomodulatory potential. With this method, the scientists identified Crizotinib, an FDA approved drug for non-small cell lung cancer, to have a previously unknown immunomodulatory potential.
Gregory I. Vladimer, Berend Snijder, Nikolaus Krall, Johannes W. Bigenzahn, Kilian V.M. Huber, Charles-Hugues Lardeau, Kumar Sanjiv, Anna Ringler, Ulrika Warpman Berglund, Monika Sabler, Oscar Lopez de la Fuente, Paul Knöbl, Stefan Kubicek, Thomas Helleday, Ulrich Jäger, and Giulio Superti-Furga. Global survey of the immunomodulatory potential of common drugs. Nature Chemical Biology, April 24, 2016. DOI:10.1038/nchembio.2360
This study was supported by the European Research Council, the Austrian Science Fund (FWF), Swiss National Science Foundation, European Molecular Biological Organization, the Austrian Federal Ministry of Science, Research and Economy, The National Foundation for Research, Technology and Development, The Swedish Cancer Society, the Kunt and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, and the Marie-Sklodowska Curie Fellowships.
March 07, 2017
Kickoff for Pharmacoscopy – a novel tool for precision medicine
In light of the importance of research on precision, molecular, and personalized medicine, CeMM and the Medical University of Vienna hosted on March 6, 2017 a kick off meeting to celebrate the start of Pharmacoscopy, a novel high-content screening and imaging platform to break resistance of relapsed and refractory hematological malignancies - a true bench-to-bedside circle.
This meeting presented and celebrated the collaborative project between the Superti-Furga and Kubicek laboratories at CeMM and the Division of Hematology and Hemostaseology, Department of Internal Medicine I of the medical University of Vienna. The Pharmacoscopy platform is funded with the precision medicine grant from the WWTF (Wiener Wissenschafts-, Forschungs- und Technologiefonds / Vienna Science and Technology Fund) awarded to Giulio Superti-Furga and Ulrich Jäger.
The meeting began by reviewing the importance of the strong CeMM and MedUni Wien collaborative atmosphere that has propelled basic and translational science, as reiterated by the Vice Rector for Research and Innovation Michaela Fritz. Christoph Zelinski, Director of the Department of Internal Medicine I, touched upon ongoing precision medicine programs in the MedUni Wien such as the EXACT trial. Ulrich Jäger, Head of the Division of Hematology and Hemostaseology, further spoke about the need for personalized and precision medicine in the hematological space, where functional testing that will be used to meet the aims of the WWTF grant can synergize with genetic testing that is clinically routine.
CeMM scientific Director Giulio Superti-Furga and his Senior Postdoctoral Fellow Gregory Vladimer outlined the image-based screening platform that is the backbone of this program, and how the technology is currently being used for clinical utility. The meeting was finished by Ulrich Jäger presenting interim results of an ongoing clinical study aimed at describing the benefits of data generated through this collaboration for the treatment of patients.
The Pharmacoscopy project aims to break resistance of refractory blood cancers through ex vivo automated image-based analysis of drug action, and potentially drive clinical trials of already approved drugs in off-indication blood cancers. The approach provides a very concrete and actionable platform for precision medicine and the use of off-indication approved drugs for late stage hematological malignancies. The collaboration is tuned directly to unmet clinical needs of resistant blood cancer patients.
January 16, 2017
Giulio Superti-Furga new Member of Scientific Council of the European Research Council (ERC)
Giulio Superti-Furga, Scientific Director of CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor for Medical Systems Biology of the Medical University of Vienna has been appointed Member of the Scientific Council of the ERC, on the 10th anniversary of its existence, for a function period of 4 years.
The European Research Council is the most important and prestigious funding institution for basic research in any field conducted within the European Union. Excellence is the sole criterion for selection; there are neither thematic priorities, nor geographical or other quotas for funding. Perhaps the most important funding programme of the ERC is the ERC Starting Independent Research Grant, promoting early scientific independence of promising talents with 2 million Euros over a period of 5 years. It has created a very positive impact on the attractiveness of Europe as research area. But the ERC has also other programmes, such as the ERC Advanced Investigator Grant, which fosters innovation carried out by established scientists with a proven scientific track record of excellence. Having been awarded two ERC Advanced Investigator Grants over the years and two ERC Proof-of-Concept Grants, to explore the application potential of research ideas, Giulio Superti-Furga, who also acted as ERC panel member in the past, knows the ERC well and is well suited to offer his experience to the organization that this year celebrates its 10th anniversary.
The ERC is governed by the Scientific Council, consisting of eminent European scientists and scholars including Nobel Prize laureates. Members are nominated by an independent search committee and appointed by the European Commission. Since 2014 Professor Jean-Pierre Bourguignon, a renowned French mathematician, is President of the European Research Council. From 2010 to 2013 Professor Helga Nowotny, a Viennese Professor of Social Studies of Science held this prestigious position. She was also a founding member of the ERC in 2007. In 2017 the European Research Council is celebrating its 10th anniversary.
The ERC Scientific Council acts on behalf of the scientific community in Europe to promote creativity and innovative research. Giulio Superti-Furga: “It is a great honor to accept this important responsibility, which has had a tremendously positive impact on basic research in Europe. My aspiration is to contribute to a more science and innovation-friendly climate in Europe by promoting excellence in research and ensuring that politicians protect and promote the ERC as the most successful research funding scheme of the EU. Results from basic research accompany us at every step and should therefore become a core theme in everyday life - in education, in the media and in public discussions. Society and politics must have the courage to invest in new projects, to keep pace with scientific developments and associated implications. It is important to understand science as a fundamental component of our culture and of our future and a motor for innovation and competiveness also for the European industry."
March 18, 2016
2nd ERC Advanced Investigator Grant
Giulio Superti-Furga, scientific director at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor of Medical Systems Biology at the Medical University of Vienna is to receive the Advanced Investigator Grant of the European Research Council ERC in the amount of approximately 2.5 million euro. The term for the prestigious grant is 5 years.
"ERC Grants are the most important promotions for life sciences in Europe. Unfortunately, the situation is becoming increasingly competitive due to budget cuts," says Giulio Superti-Furga who has built up and is leading CeMM at the campus of the Medical University of Vienna and the Vienna General Hospital: "I am all the more delighted to receive this extraordinary distinction as it also confirms the relevance and quality of CeMM research." The goal of CeMM is to prepare the precise medicine of the future by decoding molecular causes for important diseases such as cancer, inflammation and immune disorders. Giulio Superti-Furga already received an ERC Advanced Grant in 2009 for the exploration of basic immune system mechanisms. In 2011, he also received the first ERC Proof of Concept Grant in Austria.
The molecular system biologist has been granted the present ERC funding for research into existing components in cell membranes that transport dissolved substances into cells. Previous studies have shown that these "cell gates", so-called SoLute Carrier Proteins (SLCs) perform an important task in regulating the cellular metabolism and are responsible for accepting medications. The goal of the research project with the title "Game of Gates" is to decode the previously unknown rules according to which cells open or close their gates, either permitting or preventing the entry of substances. Giulio Superti-Furga: "Thus far, SLCs were treated more or less as second-rate by the scientific community. However, we expect that insights from our study will significantly contribute to a new, fundamental understanding of cellular physiology and thus prepare the way for the development of new, targeted therapies for various illnesses."
The ERC Advanced Investigator Grant is being awarded to Giulio Superti-Furga after two ERC Starting Grants had been given to Andreas Bergthaler and Christoph Bock in the autumn of 2015. Moreover, CeMM Principal Investigator Kaan Boztug won the bid – also in the autumn of 2015 – for founding the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases. The "Vienna Research Groups for Young Investigators" grant of the Vienna Science and Technology Fund WWTF had also been awarded to the CeMM PI Jörg Menche. All of these promotions once again emphasize the excellent work being performed at the CeMM.
September 21, 2015
A “hot” approach for understanding drug action and identifying new drug targets
How do successful drugs actually work? And how can we identify new targets for drug discovery to enable the development of novel potential therapeutics? A key challenge for scientists in academia and the pharmaceutical industry is to find out how small molecules such as drugs or cellular metabolites act within a cell – who are the mediators and effectors required for a drug or metabolite to exert their effect e.g. on cell proliferation, shape etc.? Based on the simple fact that interaction between a small molecule - such as a drug - and a given target protein increases the thermal stability of that protein, scientists at CeMM have developed a new state-of-art approach to reveal the cellular proteins that are engaged by small molecules and metabolites. By refining the established cellular thermal shift assay (CETSA) approach in which cells are treated with a small molecule and then heated to measure the differential protein stability upon target engagement and combining it with modern protein mass spectrometry a broad view of small molecule-protein interactions is provided. A particular advantage of the new methodology is the fact that the assay works with intact living cells and thus reflects a more natural (“physiological”) context in which the small molecule and its target proteins interact without any interference considering compound uptake, efflux, metabolism as well as cellular compartments. A potential future application includes the use of patient material to identify patient specific bio markers to enable personalized medicine.
Kilian V M Huber, Karin M Olek, André C Müller, Chris Soon Heng Tan, Keiryn L Bennett, Jacques Colinge, Giulio Superti-Furga. Proteome-wide drug and metabolite interaction mapping by thermal-stability profiling. Nature Methods, doi:10.1038/nmeth.3590.
CeMM gratefully acknowledges funding from the Austrian Academy of Sciences, the European Union (FP7 259348, ASSET) and from the Austrian Science Fund (FWF F4711, MPN).