An important group of genes that is frequently mutated in cancer consists of kinases, which mediate communication within cells. As enzymes, kinases are promising candidates to target for cancer therapy and as such, by identifying interactions between kinases and chemotherapeutic drugs the treatment for cancer could be improved. A research team, led by CeMM PI Joanna Loizou, together with colleagues from the Francis Crick Institute and King´s College, London has now established a catalog of the human kinome in response to different types of genotoxic stress.
Chemotherapy is one of the standard treatments for cancer, and one of the main challenges in cancer treatment is to find means of causing maximum damage to cancer cells with minimum damage to normal cells, by identifying specific cancer vulnerabilities. A group of proteins known to play an important role in the DNA damage response is kinases. Indeed, many kinases are mutated in a variety of human cancers. However, when taken as a whole, it is apparent that the large majority of kinases are understudied. In their recent study, first author Michel Owusu, former PhD Student in Joanna Loizou´s group, and his colleagues, focused on inactivating mutations in kinases generated by CRISPR-Cas9.
By inactivating all possible kinases in human cells and treating them with different types of DNA damaging chemotherapeutic drugs they uncovered vulnerabilities to certain types of DNA damage. This is particularly important for genes such as MARK3 or EPHB6, which are less characterized and yet commonly inactivated in the development of cancer.
In addition, the researchers characterized the effect of selected chemotherapeutic drugs on cancer cells in regards to growth, death, cell cycle and DNA damage. They revealed that within cells, MARK3 mediated communication after DNA damage. In the absence of MARK3, this communication was disrupted, leading to increased death of cancer cells after treatment with DNA damaging chemotherapeutic drugs. Thus, MARK3 is a potential novel biomarker in the treatment of cancer.
The study “Mapping the human kinome in response to DNA damage” was published online in Cell Reports, on 15 January 2019, DOI: doi.org/10.1016/j.celrep.2018.12.087
Authors: Michel Owusu, Peter Bannauer, Joana Ferreira da Silva, Thanos P. Mourikis, Alistair Jones, Peter Májek, Michael Caldera, Marc Wiedner, Charles-Hugues Lardeau, André C. Mueller, Jörg Menche, Stefan Kubicek, Francesca D. Ciccarelli and Joanna I. Loizou
Funding: The study was funded by the Austrian Federal Ministry of Science, Research and Economy, the National Foundation for Research, Technology, and Development and Austrian Science Fund (FWF).
Facial tumors of Tasmanian devils belong to the extremely rare cases of transmissible cancers. Nevertheless, they are highly interesting for biomedical research, as they allow the study of fundamental properties of cancer cells and their interaction with the host´s immune system. Scientists at CeMM, the Vienna University of Veterinary Medicine, the Medical University of Vienna and the LBI for Cancer Research were able to elucidate key molecular mechanisms that are crucial for the transmissibility of the tumor cells. The study „The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease” was published in Cancer Cell, on 14 January 2019, DOI: 10.1016/j.ccell.2018.11.018.
Tumors usually grow exclusively in the organism where their cell of origin derives from. The same applies for human cancers: apart from some rare cases, like the accidental transmission by a cut during surgery, there a no reports on contagious cancer cells. A multitude of molecular safety measures of the immune system is responsible for rejecting and destroying any foreign tissue.
An exception to this nearly universal rule exists among Tasmanian devils, the world’s largest living carnivorous marsupial. Since two decades, a deadly facial tumor is spreading at a rapid pace among the animals that killed according to current estimates around 90 percent of the wild population. Peculiarly, the cancer cells are transmitted from one Tasmanian devil to the other by bites. All collected tumor samples are genetically nearly identical and derive presumably from a single cell of origin.
How this cancer became transmissible and by what means it escapes the immune system of its otherwise healthy hosts puzzled scientists since the discovery of the mysterious disease. The scientists found that receptor molecules on the surface of the cancer cells, so-called ERBB receptors, show massively increased activity. Those receptors trigger a biochemical chain reaction within the cells that eventually activates STAT3 proteins, transcription factors that alter the cell’s genetic program. The result is an extensive rebuild of the cell: The number of molecules serving as identification for the immune system are reduced, while at the same time proliferation is accelerated and factors for metastasis of the tumor cells are produced.
Publication: Lindsay Kosack*, Bettina Wingelhofer*, Alexandra Popa*, Anna Orlova*, Benedikt Agerer, Bojan Vilagos, Peter Majek, Katja Parapatics, Alexander Lercher, Anna Ringler, Johanna Klughammer, Mark Smyth, Kseniya Khamina, Hatoon Baazim, Elvin D. de Araujo, David A. Rosa, Jisung Park, Gary Tin, Siawash Ahmar, Patrick T. Gunning, Christoph Bock, Hannah V. Siddle, Gregory M. Woods, Stefan Kubicek, Elisabeth P. Murchison, Keiryn L. Bennett, Richard Moriggl*, and Andreas Bergthaler*. The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor. Cancer Cell 35, 1-15 January 14, 2019. DOI: 10.1016/j.ccell.2018.11.018.*These authors contributed equally.
The study was funded by the Austrian Academy of Sciences, the Austrian Science Fund (FWF), the European Research Council (ERC) and the Austrian Research Promotion Agency (FFG).
Thank you to our collaborators, partners and friends for all the support and dedication to science in 2018! CeMM wishes you enjoyable holidays, and a successful start into the New Year!
Population trends and the global sustainable development goals
The 9th S.M.A.R.T. Lecture held by Professor Wolfgang Lutz, Founding Director of the Wittgenstein Centre for Demography and Global Human Capital (IIASA, VID/ÖAW, WU), was a plea for education. Particularly female education not only connects to a decrease of child mortality and to an increase of life expectancy, it proves to be key to the alleviation of poverty.
In his talk, Wolfgang Lutz proclaimed that essentially people are not very different all over the world. However, we face a universal development of “demographic modernization” with countries currently at different stages of the same process: In the first stage falling death rates due to better sanitation and medical advance together with a culturally determined high birth rate result in a high population growth. In a later stage of development birth rates also fall, leading to low or even negative population growth. By the examples of the demographic transition of Finland from 1722-2017, birth and death rates at Mauritius from 1875 on, and a study on the effect of income or education on the infant mortality in India Wolfgang Lutz impressively showed the effect of education on a higher life expectancy: When it comes to survival, mind matters more than money!
Empirical studies show that the most transformative social changes are associated with the spread of universal female literacy, and the future of world population growth and adaptive capacity to environmental change will crucially depend on female education. The “homo sapiens literata” (MPI-EVA, McElreath) - a sub-species of homo sapiens characterized by high abstraction, literacy, codified knowledge, complex socio-economic institutions and modern science - makes the change. A lively discussion followed the talk, which will continue at CeMM: How can we contribute to a positive societal development? Education matters!
We thank Professor Lutz for his inspiring talk within the S.M.A.R.T. lecture series at CeMM!
Following internal discussions at CeMM on human genome editing – prompted by recent reports on the birth of gene-edited babies using CRISPR technology in China – we distance ourselves from human trials performed without adequate ethical approval by the responsible institutions and in violation of both local regulations and the international consensus in the scientific community.
CeMM welcomes responsible research on understanding and advancing genome editing technology including CRISPR, which greatly benefits basic biomedical research and has great potential also for the treatment of many genetic diseases. Importantly, any such research must be performed in strict concordance with local, national, and international laws and regulations. Furthermore, it should be discussed and supported by the international scientific community, including biologists and medical researchers as well as ethicists, social scientists and various stakeholders of civil society, such as patients’ organizations.
There is broad consensus within the scientific community that editing of the human germline for human enhancement is entirely unacceptable. In contrast, genome editing to correct severe genetic diseases may be acceptable if there is a clear positive risk-benefit ratio, no suitable alternatives, comprehensive preparatory work supporting feasibility, full legal and regulatory compliance, and strong framework of ethical guidance and supervision.
CeMM is committed to participate in a broad societal dialog about CRISPR technology, genome editing, and other developments in the life sciences. It is important that these developments are not happening in perceived or actual secrecy at highly specialized research institutions, but that they are part of a broad discussion about chances and risks, and based on information, education and divulgation on all scientific, medical, ethical and societal aspects associated. CeMM is committed in fostering this debate and promoting genetic literacy in the general population.
To read more about the potential applications of CRISPR technology, and the use of it at CeMM, please download the full statement.
Kaan Boztug, Director of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), is awarded a prestigious Consolidator Grant of the European Research Council (ERC) for research on human immune dysregulation.
Kaan Boztug, Director of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Adjunct PI at CeMM and Professor of Pediatrics at the Medical University of Vienna and St. Anna Children’s Hospital, receives the renowned funding by the ERC with a project duration of five years to decode disorders of the human immune regulation. After being granted a FWF START prize and an ERC Starting Grant in 2012, Kaan Boztug’s research is now funded for the second time by the ERC. This shows recognition of the excellent work of Prof. Boztug’s research group, who is regarded as an international expert in the field of rare diseases of the immune system and hematopoiesis.
Why does the human body attack itself sometimes? What causes problems in the regulation of the immune system? And why are these disorders often leading to cancer? How can these insights be used to develop targeted therapies in the future? Kaan Boztug and his team try to answer these questions. The goal is to identify novel genetic factors for autoimmune disorders – diseases where the body is not able to distinguish between the body’s own cells and cells of invading pathogens. Kaan Boztug hypothesizes that the number of pathways involved is finite: “My goal is to create a map showing as many genes and pathways as possible that play a role in disorders of the balance of the immune system. This marks the foundation of further research activities and will lead to starting points for novel therapies.”
ERC Consolidator Grant
Project funding by the European Research Council (ERC) ranks among the most prestigious fundings within Europe. The Consolidator Grants are awarded up to two million euros and are intended to support excellent researchers by securing their independence and developing a successful career path. Kaan Boztug’s Consolidator Grant is already the 10th funding by the ERC for (Adjunct) PIs at CeMM.
The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD) was launched by the Ludwig Boltzmann Gesellschaft in April 2016 together with its partner institutions including the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, the Medical University of Vienna and the Children’s Cancer Research Institute and the St Anna Children’s Hospital Vienna. Its research remit is the thorough analysis of rare diseases of the hematopoietic system, the immune system and the nervous system – as such not only dedicated to provide research for the development of personalized therapeutics for affected patients, but with similar efforts dedicated to unravel novel insights into human biology. Benefitting from full access to the infrastructure of its partner institutions, LBI-RUD has established a coordinated research programme, integrating and considering scientific, sociologic, ethical and economical aspects of rare diseases. www.rare-diseases.at
We congratulate Kaan Boztug and his team!
Do you want to work in an environment that promotes free-minded scientific creativity, and translate your findings to impact medical practice and improve healthcare?
Are you excited to gain a new understanding of the molecular physiology and pathology of humans?
Do you want to join an international group of highly collaborative and successful colleagues that help you achieve your training and research goals?
Are you a person who enjoys teamwork across disciplines and within a broader cultural and social context?
The next PhD Program of CeMM, the Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna will start in October 2019. We are offering 15 fully funded PhD positions at CeMM and LBI-RUD and are looking for exceptionally motivated candidates!
Medics, Biologists, Chemists, Bioinformaticians, Computer Scientists, Engineers, Physicists, Mathematicians, and candidates with a degree in a similar subject please apply now.
CeMM and LBI-RUD, the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases are partner institutes and 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 and the arts. The institutes are located in the very same research building at the center of one of the largest medical campuses in Europe.
The 2019 CeMM PhD Program will focus on the thematic areas of Infection, Immunity, Metabolism, Cancer, Rare Diseases, Network Medicine, and Design Chemistry. These areas are built on the pillars of epigenetics and genome integrity, bioinformatics and systems biology, high-throughput genetics, genomics and proteomics, molecular and cell biology, chemical biology, organic and inorganic chemical synthesis.
For more information please visit: www.cemm.at/phd-program
Application Deadline: 7th January 2019
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).