Maria Sibilia, Head of the Institute for Cancer Research at MedUni Vienna, who is conducting a 60-month project entitled "TNT Tumors" (total funding 2.5 million euros), is looking at immunomodulation of the innate immune system to fight cancer. The concept is to modulate innate immune cells, such as plasmacytoid dendritic cells (pDC) and Tumor-Associated Macrophages (TAM) so that they attack tumors, thereby enhancing the effect of standard cancer treatments.
Recent advances using immune checkpoint inhibitors demonstrate the great potential of immunemodulation in cancer and metastasis treatment.
However, the effective treatment of only a subset of patients shows that this is only the start to utilize the power of the immune system to fight cancer. An interesting approach is to harness innate immune cells, such as plasmacytoid dendritic cells (pDCs) and tumor-associated macrophages (TAM) to attack tumors and to enhance the effect of standard anti-cancer therapies. Recently, using mouse models we identified two independent mechanisms by which modulation of these two cell types restrained tumor growth. First, the direct killing of tumor cells by pDCs that occurs independent of the adaptive immune system. Second, we identified a tumor-promoting role of EGFR-expressing (EGFR+) TAMs during tumorigenesis. This enables us to look at the role of EGFR in tumorigenesis in a completely new way and we plan to exploit this novel finding to reevaluate the mechanism by which anti-EGFR drugs are effective in tumors.
The mechanisms endowing pDCs with tumor-killing capacities and determining the specificity of tumor cell recognition by activated pDCs are poorly understood. Furthermore, the interaction of pDCs with macrophages has never been investigated in tumors. Here I propose to define the molecular mechanisms by which pDCs and TAMs can be instructed to adopt an anti-tumorigenic phenotype. Inducible and cell-specific genetic mouse models mimicking human cancers will allow to molecularly dissect the immunemodulatory capacity of pDCs and TAMs.
State-of-the-art large scale in vitro and in vivo RNAi screens will provide a platform to identify novel molecular pathways and open the possibility for testing new strategies in cancer immunetherapy. The clinical significance of our findings will be validated in human cancer samples in close cooperation with clinicians, which ensures a fast predictive and therapeutic translation of our results.
"Game of Gates"
Giulio Superti-Furga, Scientific Director of the CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences and Professor of Medical Systems Biology at MedUni Vienna, will receive a European Research Council ERC Advanced Grant of around 2.5 million euros. This prestigious funding runs for a term of 5 years.
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."
Tibor Harkany, Head of the Department of Molecular Neurosciences at the Center for Brain Research at MedUni Vienna, will receive an Advanced Grant of 2.5 million euros for his "Secret Cells" project for the next five years.
This ERC programme focuses on new methods, based on the cellular, network and behavioral levels, to determine the extent of neuronal heterogeneity in the hypothalamus.
The mammalian brain controls bodily responses to environmental challenges, including metabolic needs and stress (survival) responses, The hypothalamus is the brain’s center to orchestrate specific adaptations, which are achieved through an exceptional heterogeneity of nerve cells. As such, each hypothalamic neuron responds to a subset (or single) stressor by a) producing executive commands through hormone release into the general circulation and b) being wired into neuronal networks that allow for, e.g., conscious representation and behavioral changes.
Despite a century of research, our knowledge of neuronal diversity in the hypothalamus, and how this cellular code confers functional specificity remain incomplete. This advanced ERC work program will use novel methods at the cellular, network and behavioral levels to define the extent of neuronal heterogeneity in the hypothalamus. Next, an attempt will be made to define the identity of secreted substances from novel neuronal subtypes and their mechanism of action in both brain and periphery. Since the release of any known neurotransmitter/peptide involves a set of specific proteins, we will take advantage of recent discoveries on a family of “sensor proteins” (that link the input signal with secretion event) to determine specific molecular determinants of hormone secretion. Overall, we expect to significantly advance knowledge on the central regulation of metabolic responsiveness of the human body, which underscore the survival of our species.
Ten ERC grants have now been awarded to MedUni Vienna researchers. ERC grants are currently held by the following scientists: Alwin Köhler, Thomas Klausberger, Bernhard Baumann, Igor Adamejko, Maria Sibilia, Tibor Harkany, Giulio Superti-Furga, Kaan Boztug, Christoph Bock and Andreas Bergthaler.
The European Research Council (ERC) offers generous research prizes (of two million euros, on average) to fund basic research. It awards: Starting and Consolidator Grants for young scientists and Advanced Grants for established researchers. The Starting and Consolidator Grants are intended to help young researchers to establish themselves as independent researchers while the Advanced Grants are for established scientists, who want to use this funding to implement advanced and complex research projects.