September 14, 2019

CeMM PI Andreas Bergthaler nominated "Austrian of the Year 2019, Category Research"

We congratulate CeMM PI Andreas Bergthaler, who has been nominated “Austrian of the Year 2019” in the "Research" category. Join us in supporting Andreas’ work and nomination!

Vote for Andreas Bergthaler via the online system.

The #Austria19 award is organized by the newspaper Die Presse in collaboration with the ORF, the Austrian Broadcasting Cooperation, and is given to individuals who made outstanding contributions in the fields of science, economics and humanity. 

The research of Andreas and his team focuses on how inflammatory processes are regulated and how the immune system responds to viral infections. At CeMM, he has already gained important new insights into the molecular understanding of hepatitis, pneumonia and metabolic diseases in infections.

Andreas Bergthaler studied veterinary medicine in Vienna. He undertook graduate and postgraduate research with Hans Hengartner and Nobel Laureate Rolf Zinkernagel at the University of Zurich and ETH Zurich followed by postdoctoral positions at the University of Geneva and the Institute for Systems Biology in Seattle. He is recipient of an ERC Starting Grant and several awards including the Löffler-Frosch-Prize of the Society of Virology (2016), the Georges-Köhler Prize of the German Society for Immunology (2016), the Seymour and Vivian Milstein Young Investigator Award of the International Cytokine and Interferon Society (2016) and the Austrian Infection Research Prize of the Austrian Society for Infectious Diseases and Tropical Medicine (2017). Andreas Bergthaler co-founded the clinical-stage immunotherapy company Hookipa Pharma. He joined CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences as Principal Investigator in 2011.

This is the second time a CeMM researcher has been nominated for this public voting. In 2011, CeMM’s Scientific Director, Giulio Superti-Furga, received the award in the same category for bringing scientific excellence and innovation to Austria.  

September 03, 2019

ERC Starting Grant for CeMM PI Georg Winter

Georg Winter, CeMM Principal Investigator has received a prestigious Starting Grant of the European Research Council (ERC) for his research proposal “Glue2Degrade: Therapeutic hijacking of E3 Ligases”. The project will be funded with 1.3 € million over a period of five years.

With his research proposal Georg Winter addresses a timely and important problem, trying to fill a gap in drug development and cancer research. The Glue2Degrade project aims to transform the pharmacologically targetable space of the proteome. The project is built on the hypothesis that small molecules that can induce targeted protein degradation are much more prevalent than currently anticipated. Georg’s proposal focuses on the identification of so-called “molecular glues”, which degrade proteins by inducing cooperative protein binding to E3 ubiquitin ligases. This opens up the potential for therapeutic development of cell-, tissue-, and cancer-type specific degradation of otherwise undruggable proteins.

Traditional drug design relies on inhibition of enzymes or receptors with accessible hydrophobic pockets. Hence, most existing small-molecules are limited to the traditional “key and keyhole principle”. Unfortunately, only about 20% of all proteins can be targeted via this strategy. The concept of chemically targeting proteins for their degradation promises to overcome this limitation. In the Glue2Degrade proposal, Georg wants to revolutionize the field of targeted protein degradation to be able to chemically hijack many new E3 ligases in an unprecedented manner. As a result, his research is expected to deliver novel therapeutic strategies to target cancer as well as a fundamental understanding of mechanisms governing cellular protein degradation.

Georg Winter, PhD, obtained his degree from the Medical University of Vienna, working on elucidating the mechanism of action of anti-cancer drugs under the supervision of Giulio Superti-Furga at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. He specialized on proteomics- as well as chemical genetics approaches to identify drug resistance mechanisms and synergistic drug combinations. He continued his training in chemical biology, working as a postdoctoral fellow with James Bradner at the Dana Farber Cancer Institute/Harvard Medical School. He innovated the first generalizable pharmacologic solution to in vivo target protein degradation (Winter et al., Science 2015). He was recruited as a CeMM Principal Investigator in 2016 where his research is now focused on using the unique molecular pharmacology of targeted protein degradation to understand and disrupt aberrant gene control in human cancers. Georg Winter (co-) authored 29 manuscripts including publications in Science, Nature, Nature Chemical Biology, Nature Genetics, Elife and Molecular Cell. Georg Winter’s contribution to the field of targeted protein degradation was acknowledged via multiple prizes and awards, including the Eppendorf Award 2019 and the Elisabeth Lutz Award of the Austrian Academy of Sciences.

Project support by the European Research Council (ERC) ranks among the most prestigious fundings within Europe. An ERC Starting Grant is meant for promising early-career researchers with two to seven years’ experience after PhD. Excellence is the sole criterion for selection, and there are neither thematic priorities, nor geographical quotas for funding. The aim is to recognize the best ideas, and confer status and visibility to the best research and talents in Europe.

CeMM congratulates Georg Winter and his team to this great achievement and the well-funded grant!

September 02, 2019

Obituary Daniel Lackner

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With great sadness, we have to inform you about the passing of Daniel Lackner, who died on 31 August 2019, at the age of 41, after severe illness. Daniel started at CeMM as RESOLUTE Scientific Project Manager in the group of the Scientific Director in March 2018, and will be dearly missed by his colleagues and friends. Our thoughts and deepest sympathy are with his family.

Daniel performed his undergraduate studies in biology and genetics at the MFPL in Vienna. For his graduate work he moved to the Wellcome Trust Sanger Institute in Hinxton, UK, where he used genomic approaches to study gene expression regulation in fission yeast. After obtaining his PhD from the University of Cambridge, he decided to do his post-doctoral work at the Salk Institute for Biological Studies in San Diego, USA. There, he studied telomere biology and aging with a focus on large-scale approaches. After returning to Austria in 2015, he joined the biotech company Horizon Discovery, where he led a team to generate human knock-out cell lines using CRISPR/Cas9, before he started his new role as Scientific Project Manager within the Superti-Furga lab at CeMM.

Daniel played an essential role in setting up the scientific and organizational framework of the IMI-funded EU Project RESOLUTE (Research Empowerment on Solute Carriers), a public-private partnership with 13 research groups from academia and industry. He was highly respected within the consortium for his scientific expertise, his dedicated and diligent working style, and his ability in successfully bridging academia and industry, by connecting scientists with different backgrounds and expectation for a common overarching goal.

From the very beginning, Daniel was very open about his disease and his courageous and exhausting fight against a rare tumor. Daniel was a true scientist at heart and a role model in many ways. His intellectual rigor, supportive and humorous attitude contributed positively to CeMM’s culture and the success of the RESOLUTE project.

Daniel Lackner will be dearly missed by the CeMM Directors, by his colleagues who had the privilege of interacting with him, and by the entire RESOLUTE consortium. We lose an extraordinary researcher, a talented and dedicated science manager, and highly appreciated colleague. Daniel died way too early. Our sincere condolences go to his wife and his children.

Giulio Superti-Furga and Anita Ender

August 28, 2019

Novel immunodeficiency syndrome amidst immunity and carcinogenesis

Graphical abstract as published in J Clin Invest (https://doi.org/10.1172/JCI128903), artwork by Tatjana Hirschmugl

For the first time, a study led by Kaan Boztug, Scientific Director of St. Anna Children's Cancer Research Institute, unveils a hitherto unknown immune deficiency syndrome, which is based on a reduced functionality of the enzyme complex polymerase δ, an essential controller in DNA replication. Mutations affecting its function lead to genomic instability, neurodevelopmental disorders and immunodeficiency. The study was recently published in the prestigious Journal of Clinical Investigation and brings important insights into adaptive immunity and carcinogenesis.

Genes are the basic building blocks of life and, consequently, essential to all living organisms. The factors, which are responsible for their duplication, are very similar in almost all living organisms and have hardly changed over thousands of years. One of these factors is polymerase δ. This enzyme complex is a key element not only for DNA replication, but also for genome stabilization and cell cycle regulation. Polymerase δ is composed of four building blocks: POLD1 and the additional subunits POLD2, POLD3 and POLD4. Organisms with severe disruption of these DNA polymerases are often not viable, which makes research difficult.

Led by Kaan Boztug, researchers from LBI-RUD, CeMM and MedUni Vienna, together with collaborators from the University of Istanbul and the University of Leiden, could identify two unrelated patients with a novel immunodeficiency syndrome based on a reduced functionality of polymerase δ. Specifically, they detected biallelic germline mutations, i.e. gene mutations inherited from both parents, in POLD1 and POLD2. In both cases, these mutations resulted in an immunodeficiency syndrome with recurrent respiratory infections, skin problems, and neurodevelopmental disorders. Closer examination of the disease mechanisms revealed that the cell cycle was impaired in the lymphocytes of both patients. The number of copying errors in DNA increased, which lead to warning tags in the DNA of the cell, and, therefore, causes cell cycle dysfunction.

Particularly noteworthy is that the study provides also key information for other diseases such as childhood cancer: Unlike in other immunodeficiency syndromes with a shortage of an immune-specific factor, the underlying disease mechanism is a deficiency of a basic function of the cell. Although the deficiency particularly affected immune cells, the replication control mechanism of polymerase δ is relevant to the function of all cells. A disorder can have dramatic consequences in the balance of cell growth. It is known that certain mutations in POLD1 lead to the so-called "mutator phenotype", which contributes to genetic instability and is found in many human cancers. Accordingly, POLD1 is classified as a highly dangerous cause of cancer in the international classification. Conversely, the congenital POLD1 / 2 mutations described in the study lead to a reduced intrinsic activity (the "actual task") of the polymerase δ and possibly increases the chances of developing cancer at an earlier age (cancer predisposition syndrome). The present study also aims to bring awareness into the research and help identify additional patients for a systematic analysis of the cancer risk in affected children and children with related illnesses.

The Study: "Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress” was published in the Journal of Clinical Investigation on 26 August 2019, DOI: 10.1172/JCI128903

Authors: Cecilia Domínguez Conde*, Özlem Yüce Petronczki*, Safa Baris*, Katharina L. Willmann*, Enrico Girardi, Elisabeth Salzer, Stefan Weitzer, Rico Chandra Ardy, Ana Krolo, Hanna Ijspeert, Ayca Kiykim, Elif Karakoc-Aydiner, Elisabeth Förster-Waldl, Leo Kager, Winfried F. Pickl, Giulio Superti-Furga, Javier Martínez, Joanna I. Loizou, Ahmet Ozen, Mirjam van der Burg, and Kaan Boztug

Funding: The study was funded by the European Research Council (ERC) under the European Union Seventh Framework Program (FP7/2007-2013; ERC grant agreement 310857, to KB), Austrian National Bank (ÖNB Jubilee Fund 16385, to KB), a grant from the Jeffrey Modell Foundation (to KB and MB), and the Austrian Science Fund Lise Meitner Program Fellowship (FWF M1809, to KLW).

 

August 27, 2019

A molecular "Trojan Horse"

Nuno Maulide and Stefan Kubicek on CeMM Terrace

Nuno Maulide´s group from the Faculty of Chemistry of the University of Vienna has, in cooperation with Stefan Kubicek´s lab at CeMM, achieved the synthesis of a potential immunosuppressive agent by modification of a naturally occurring compound. In this endeavour, the researchers have employed a masking trick to "hide" a reactive species inside the target molecule. The results were recently published in the renowned "Journal of the American Chemical Society".

The FR-molecules: natural products with special properties

In 2003, a Japanese company reported the isolation of 3 natural products from the microorganism Pseudomonas fluorescens, the so-called "FR Molecules". Noteworthy was their complex chemical structure but also their very interesting immunosuppressive properties. Immunosuppressive drugs are widely used in the treatment of allograft repulsions and autoimmune-associated diseases. Although a range of such drugs have been developed and are used clinically, almost all of them carry severe side effects and limitations. The search for new immunosuppressants with a distinct mode of action is therefore an urgent need to improve the safety and efficiency of immunosuppressive therapy.

Several research groups have attempted the laboratory synthesis of the FR molecules in the years that followed – with mitigated sucess. "They all struggled with the molecule’s Achiles’ Heel: the macrocyclic ring with three consecutive double bonds", explains Nuno Maulide, who since November 2018 is also Adjunct PI at CeMM.

A solution to a long-standing problem

Nuno and his team have now developed a novel chemical reaction that allows the preparation of macrocyclic structures in high efficiency and from simple precursors. "We simply hide the double bonds in a 'secured' form, so that they can be revealed at a later stage. Very much like a 'Trojan horse'", jokes Yong Chen, first author of the paper.

For this goal the researchers install a smaller ring with only 4 carbon atoms, termed a "cyclobutene", as "masked" form for the double bonds of the natural product. This approach results in a very short access to the FR molecules.

"We are now in a position to make grams of these compounds; the natural source delivered at best milligrams – a considerable advance. Furthermore, the compounds we prepare in the lab are indistinguishable from those isolated from Pseudomonas fluorescens", enthuses Nuno Maulide.

Variations lead to a better drug

As the researchers are now able to reproduce these complex structures in the lab, they are in a position to introduce non-natural variations and modifications of those structures. They already found an "analogue" (i.e, a new molecule resembling the original natural product but possessing small structural modifications) that is almost 100 times more potent than the compounds produced by Nature. "The joint collaboration between University of Vienna and CeMM has resulted in true synergies", explains Stefan Kubicek from CeMM of the Austrian Academy of Sciences, and co-author of the study.

The Study: "A domino 10-step total synthesis of FR252921 and analogues, complex macrocyclic immunosuppressants”: was published in the Journal of the American Chemical Society, DOI: 10.1021/jacs. 9b07185

Authors: Yong Chen, Guilhem Coussanes, Caroline Souris, Paul Aillard, Dainis Kaldre, Kathrin Runggatscher, Stefan Kubicek, Giovanni Di Mauro, Boris Maryasin, Nuno Maulide

Funding: The study was funded by the European Research Council (ERC, CoG VINCAT), the Austrian Science Fund (FWF, under P27194 and Doctoral Program “Molecular Drug Targets” W1232), and the German Research Foundation (DFG, Grant MA 4861/3-1).

August 22, 2019

Novel paradigm in drug development: Understanding resistance mechanisms to targeted protein degradation

Co-first authors Martin Jaeger and Cristina Mayor-Ruiz, last author Georg Winter © CeMM/Franzi Kreis

Targeted protein degradation (TPD) is a new paradigm in drug discovery that could lead to the development of new medicines to treat diseases such as cancer more effectively. A recent study by researchers at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences reveals global and drug-specific cellular effectors needed for TPD. The results have now been published in the scientific journal Molecular Cell.

Traditional medicines mostly function as inhibitors, attacking the disease-relevant proteins that cause cancer, by binding to their accessible pockets. Following this strategy, only ~20% of all proteins are chemically addressable, leaving some of the most relevant targets inaccessible to therapeutic development.

Targeted protein degradation (TPD) is a novel approach in drug development that could overcome this limitation, and currently represents a promising therapeutic strategy towards, for example, cancer treatment. TPD is based on small-molecules, generally called “degraders”, that induce the degradation of proteins by re-directing ubiquitin E3 ligases towards the protein we aim to eliminate. In other words, utilizing the cell’s Ubiquitin Proteasome System (UPS), which is our body’s natural way of seeking out and destroying damaged proteins.

Until now TPD had been mostly studied from a structural perspective. Georg Winter’s laboratory at CeMM focused on identifying and mechanistically understanding genetic determinants of sensitivity to small-molecule degraders. “We selected a representative set of five degraders, which hijack different ubiquitin E3 ligases to degrade proteins of clinical relevance, such as BRD4, CDK9, or GSPT1. Conducting resistance screens, we were able to identify genes that determine the efficacy of targeted protein degradation”, explains Cristina Mayor-Ruiz, CeMM postdoc and co-first author of the study.

The data obtained identify central UPS regulators as essential for degrader efficacy. “When those proteins are perturbed, ubiquitin E3 ligases lose their ability to flexibly assemble and disassemble in response to cellular needs. Instead, they start tagging themselves for destruction in a process called auto-degradation. As a consequence, the tested degrader drugs fail to destabilize their target proteins and are ineffective in blocking cancer cell growth”, elaborates Martin Jaeger, CeMM PhD student and second co-first author of the study.

The research conducted by Cristina Mayor-Ruiz, Martin Jaeger et al. combining functional genomics and quantitative proteomics is the first study that comprehensively dissects cellular determinants of mechanistically different small-molecule degraders, bringing new light into their rational design.

Now that degraders are entering the clinic, understanding potential resistance mechanisms may inform on ways to overcome it. The modulator gene-networks that we have identified can serve as biomarkers to support patient stratification, but also teach us a lot about fundamental aspects of the regulation and dynamics of the protein degradation machinery”, says Georg Winter, CeMM Principal Investigator.

The study “Plasticity of the cullin-RING ligase repertoire shapes sensitivity to ligand-induced protein degradation” was published in Molecular Cell on 22 August 2019. DOI: 10.1016/j.molcel.2019.07.013

Authors:
Cristina Mayor-Ruiz*, Martin G. Jaeger*, Sophie Bauer, Matthias Brand, Celine Sin, Alexander Hanzl, André C. Mueller, Jörg Menche, Georg E. Winter

Funding:
The study was funded by the Austrian Academy of Sciences. Cristina Mayor-Ruiz was supported by an EMBO long-term fellowship (EMBO-LTF ALTF 676-2017) and Martin Jäger was supported by a Boehringer Ingelheim Fonds (BIF) PhD fellowship.

August 21, 2019

CeMM International Postdoc Program (Vienna, Austria)

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Pre-ERC Postdoc Program in Cellular, Molecular and Digital Medicine

We are recruiting a group of postdocs (13 positions available) who are eager to pursue groundbreaking biomedical research, and we will help them to establish themselves as future scientific leaders. This postdoc program is designed to prepare postdoctoral researchers for a successful ERC Starting Grant application and for an independent research career in top research organizations in Europe and around the world.

The postdoc program is based at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna, one of Europe’s leading centers for basic biomedical research – with clinical translation in mind. Selected candidates will join one of CeMM’s research groups for 3 to 6 years, addressing ambitious research questions in areas such as cancer, immunology, chemical biology, epigenetics, metabolism, and genomic medicine. Research projects will focus on medically relevant problems, including disease mechanisms, modern therapeutics and diagnostic strategies. On top, postdocs will receive extensive career development and leadership training from the entire CeMM Faculty and additional experts in a highly collaborative and supportive environment.

Potential projects:

Host pathogen interactions (Bergthaler Lab); Mechanistic investigations of the dynamic evolution of chronic viruses

Immunometabolism (Bergthaler Lab); Metabolic inter-organ communication during inflammation and infection

Cancer immune modeling (Bock Lab); Single-cell analysis of immune deregulation in (humanized) mouse models of cancer

Human synthetic biology (Bock Lab); Developing new cell-based therapies (CAR T etc.) using combinatorial bioengineering and machine learning / artificial intelligence

Precision pediatric oncology (Boztug Lab); Integrating multi-omics profiling with ex vivo image-based drug sensitivity testing for personalized therapies

Organoid-omics (Boztug Lab); Profiling patient organoids from inherited rare diseases and pediatric cancer patients for precision medicine

Chemical epigenetics (Kubicek Lab); Developing novel chemical probes targeting cancers with mutations in chromatin modifiers

Nuclear metabolism (Kubicek Lab); Studying the role of chromatin-bound metabolic enzymes in leukemias

Cellular transporters (Superti-Furga Lab); Targeting cellular transporters to modulate disease

Systems biology (Superti-Furga Lab); Network-based systems-level analysis of the human transportome

Cancer biology (Villunger Lab); Interrogating the PIDDosome in ploidy control for tumor suppression

Polyploidization in health and disease (Villunger Lab); The role of polyploidy in heart development and regeneration

Targeted protein degradation (Winter Lab); Medicinal chemistry strategies to modulate the proteolytic machinery for cancer therapy

We are open to other ideas that fit into the broader scope and mission of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and its partner institute LBI-RUD, the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases.

More information, and a more detailed description of the #CeMMPostdocProgram
Deadline for applications: 31 August 2019

First author Sandra Schick, last author Stefan Kubicek © CeMM/Franzi Kreis

More than one-fifth of all human cancers harbor mutations in one of the members of the BAF chromatin remodeling complex. Deep biochemical and epigenomic characterization of a cell line panel comprehensively representing all these mutations enabled researchers at the CeMM Research Center for Molecule Medicine of the Austrian Academy of Sciences to identify new approaches to target BAF mutant cancers. The study describing these findings has now been published in the journal Nature Genetics.  

Chromatin organizes the approximately two meters of DNA present in the nucleus of every human cell so that, dependent on the cell type and state, certain genes can be activated, others repressed. The fundamental organizing unit of chromatin is the nucleosome, consisting of 146 base pairs of DNA wrapped around a histone octamer. Whenever a cell needs to adapt – for example, to respond to developmental or environmental signals or to DNA damage –, it needs to alter the accessibility of its DNA. Doing exactly this is the function of chromatin remodelers, enzymes that use the energy of ATP to move or evict nucleosomes. Chromatin remodeling complexes come in multiple flavors in human cells; a particularly interesting complex is the BAF complex. In fact, it is not only one complex, but many different ones. Up to 15 complex positions can be occupied by proteins encoded from 29 different genes, the combinatorics adding up to more than 10,000 theoretically possible different complexes. 

What makes the BAF complex so relevant for human disease are the mutations that are found in the BAF complex genes in approximately every fifth human cancer. Currently, we have only a limited understanding how these mutations contribute to cancer development. Even more problematic, we do not have therapies to specifically cure BAF mutant cancers. Finding such therapies is challenging, because typically the genetic aberrations are so called loss of function mutations. These result in cancer cells lacking a specific BAF subunit protein, and it is hard to develop a drug against something that is not there. 

To find ways to nevertheless target BAF mutant cells, Sandra Schick, postdoctoral fellow in the laboratory of Stefan Kubicek of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, first needed to generate a relevant cellular model. She therefore established a panel of 22 isogenic cell lines that differed only in each lacking a single different BAF subunit. In these cells, she first characterized the consequences of loss of a single subunit on complex composition, chromatin accessibility and transcription. “We identified preferential BAF complex configurations, which can be altered when single subunits are lost” said Schick. “Furthermore, there is an intense cross-talk between these subunits, so that, depending on the lost gene, other BAF subunits are incorporated with higher or lower frequency”. These data indicate that although the original mutation results in the loss of one BAF subunit, the cancer promoting properties might be conferred by aberrant functions of the remaining BAF complexes. And such aberrant functions might again be druggable. 

To test whether it is indeed the case that BAF mutant cancers become addicted to the function of the remaining complexes, the team went on to systematically deplete a second member of the BAF complexes in these cells that had already lost one subunit. From this large dataset they focused on three novel intra-complex synthetic lethalities, SMARCA4-ARID2, SMARCA4-ACTB, and SMARCC1-SMARCC2. The extensive systematic data on interaction proteomics, chromatin accessibility and transcription changes helped explain the molecular mechanism for these synthetic interactions. “But even more important to us was to prove that these novel targets hold up in relevant cancer cell lines beyond our cellular model system” explains Stefan Kubicek. And this is exactly what the researchers could prove, in a panel of 22 different cancer cell lines. “The SMARCC1-SMARCC2 pair was particularly strong and conserved, and we could show that cell lines with low SMARCC1 levels are extremely sensitive to loss of SMARCC2.” 

The project, conducted in the context of the Christian Doppler Laboratory for Chemical Epigenetics in collaboration with Boehringer Ingelheim, provided not only a deep molecular insight in the biochemical and epigenetic alterations after the loss of a BAF subunit, but also identified novel targets towards the goal of developing targeted treatments for BAF-mutated cancers.

The study “Systematic characterization of BAF mutations explains intra-complex synthetic lethalities in human cancers” was published in Nature Genetics on 19 August 2019. DOI: 10.1038/s41588-019-0477-9.

Authors:

Sandra Schick, André F. Rendeiro, Kathrin Runggatscher, Anna Ringler, Bernd Boidol, Melanie Hinkel, Peter Májek, Loan Vulliard, Thomas Penz, Katja Parapatics, Christian Schmidl, Jörg Menche, Guido Boehmelt, Mark Petronczki, André C. Mueller, Christoph Bock, Stefan Kubicek

The study was funded by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology, and Development, the Austrian Science Fund (FWF), and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme.

Stefan Kubicek is Principal Investigator at CeMM and Head of the Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives. He also leads the Chemical Screening and PLACEBO (Platform Austria for Chemical Biology) program and the Proteomics and Metabolomics Facility at CeMM.

August 01, 2019

Nature podcast with CeMM PI Georg Winter

Picture from the award ceremony at the EMBL Advanced Training Centre in Heidelberg in June 2019. Axel Jahns, Wilhelm Plüster, Laura Machesky, Georg Winter, Maria Leptin, Reinhard Jahn. Photo credit: EMBL Photolab

Listen to a Nature podcast with CeMM PI Georg Winter, this year’s Eppendorf Young European Investigators Award Winner: https://www.nature.com/articles/d42473-019-00212-6

On 27 June 2019, the ceremony for the Eppendorf Award took place at the EMBL Advanced Training Centre in Heidelberg. The laudation honoring Georg’s achievements was held by Award Jury Chairman Reinhard Jahn, Director of the Max Planck Institute for Biophysical Chemistry, Göttingen. Georg received the € 20.000 prize for his pioneering work developing a method for targeting specific proteins for degradation using heterobifunctional chemical compounds to specifically recruit ubiquitin E3 ligases to the intended protein target for destruction.

Statement of the Jury: “This powerful system enables targeting of previously undruggable targets and shows promise both in cells and in vivo in model systems as an emerging therapy. Georg Winter’s work has led to a fury of excitement across pharmaceutical companies and has resulted in several patents; it holds promise to yield novel therapies for cancer and other diseases of unmet need.”

The Eppendorf Award for Young European Investigators was first established in 1995. It acknowledges outstanding contributions to biomedical research in Europe based on methods of molecular biology, including novel analytical concepts. The Award is presented in partnership with the scientific journal Nature.

July 25, 2019

An unexpected developmental hierarchy in an unusual disease

LCH cells from a tumour biopsy, imaged with a confocal microscope. The green staining identifies the actively proliferating cells.

Langerhans cell histiocytosis (LCH) is a rare disease affecting primarily young children. While LCH may heal by itself without treatment in some patients, others require intensive chemotherapy and suffer from long-term consequences, or may even succumb to the disease. The reasons for these differences in disease severity are poorly understood. In a new study published in Cancer Discovery, researchers from the St. Anna Children’s Cancer Research Institute (CCRI) and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences revealed important insights into the cellular heterogeneity and molecular mechanisms underlying LCH.

Langerhans cell histiocytosis (LCH) is a very unusual disease: Often classified as a cancer because of uncontrolled cell growth in different parts of the body, it also has features of an autoimmune disease, as LCH lesions attract immune cells and show characteristic tissue inflammation. LCH is clinically variable and often difficult to diagnose. Skin involvement in babies with LCH can look like a nappy rash, whereas bone involvement can be mistaken as sarcoma in an X-ray picture. In its most aggressive form, LCH can present as leukaemia-like disease and lead to organ failure. These diverse manifestations and the enormous clinical heterogeneity of LCH continue to puzzle medical doctors and scientists around the world.

Studying LCH lesions under the microscope, Caroline Hutter – a paediatric oncologist at St. Anna Children’s Hospital, principal investigator at CCRI and co-lead investigator of this study – observed striking heterogeneity among LCH cells. To investigate this diversity in full molecular detail, she assembled an interdisciplinary team including experimental and computational researchers from CCRI and CeMM, as well as medical doctors from St. Anna Children’s Hospital and Vienna General Hospital. Her aim was to answer two fundamental questions: What are the mechanisms behind LCH, and how can we improve treatment of children affected by this disease?

Utilizing state-of-the-art technology in the laboratory of co-lead investigator Christoph Bock (CeMM), LCH lesions were analysed for their molecular composition at single-cell resolution. Spearheaded by one computational postdoc, Florian Halbritter (now at CCRI), and one wet-lab postdoc, Matthias Farlik (now at Medical University of Vienna), the team analysed the molecular profiles of LCH lesions and developed a comprehensive map of cellular heterogeneity in LCH.

In this molecular map of LCH, the team identified multiple LCH cell subtypes. One of these subtypes comprised actively dividing cells, which appear to give rise to the other LCH cell subtypes. In further experiments, the team unravelled the molecular pathways that are active in different branches of this unexpected developmental hierarchy, which corroborated an interplay of developmental, immunological, and oncogenic mechanisms in LCH.

The study is a significant step forward in the understanding of this enigmatic disease. In future, these finding may help devise better ways of distinguishing severe from less severe disease cases, and they may even open up new treatment possibilities.

The study "Epigenomics and Single-cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis" is published ahead of print in Cancer Discovery on 25 July 2019. DOI: 10.1158/2159-8290.CD-19-0138.

Authors: Halbritter F*, Farlik M*, Schwentner R, Jug G, Fortelny N, Schnöller T, Pisa H, Schuster LC, Reinprecht A, Czech T, Gojo J, Holter W, Minkov M, Bauer W, Simonitsch-Klupp I, Bock C#, Hutter C#. * These authors contributed equally to this work; # CB and CH jointly directed the research.

Funding: The study was partly funded by the Austrian Science Fund, the German Research Foundation, the European Research Council, the Austrian Academy of Sciences, and the Histiocytosis Association.

The St. Anna Children's Cancer Research Institute (CCRI), founded in 1988, develops and optimizes diagnostic, prognostic, and therapeutic strategies for the treatment of children and adolescents with cancer by combining basic research with translational and clinical research. The focus is on the specific characteristics of childhood tumour diseases in order to provide young patients with the best possible and most innovative therapies. Around 120 scientists and students are involved in ongoing research projects at CCRI. Dedicated research groups in the fields of tumour genomics and epigenomics, immunology, molecular biology, cell biology, bioinformatics and clinical research are working together to harmonize scientific experimental findings with the clinical needs of physicians. Every year, about 250 children and adolescents in Austria are diagnosed with cancer. Thanks to interdisciplinary research work on an international level, 70 to 80 % of the children affected can already be cured.