Project acronym ChromatinTargets
Project Systematic in-vivo analysis of chromatin-associated targets in leukemia
Researcher (PI) Johannes Zuber
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.
Summary
Recent advances in genome sequencing illustrate the complexity, heterogeneity and plasticity of cancer genomes. In leukemia - a group of blood cancers affecting 300,000 new patients every year – we know over 100 driver mutations. This genetic complexity poses a daunting challenge for the development of targeted therapies and highlights the urgent need for evaluating them in combination. One gene class that has recently emerged as highly promising target space are chromatin regulators, which maintain aberrant cell fate programs in leukemia. The dependency on altered chromatin states is thought to provide great therapeutic opportunities, since epigenetic aberrations are reversible and controlled by a machinery that is amenable to drug modulation. However, the precise mechanisms underlying these dependencies and the most effective and safe targets to exploit them therapeutically remain unknown.
Here we propose an innovative approach combining genetically engineered leukemia mouse models and advanced in-vivo RNAi technologies to explore chromatin-associated vulnerabilities at an unprecedented level of depth. Following a first screen in MLL-AF9;Nras-driven AML, which led to the discovery of BRD4 as a promising therapeutic target, we aim to (1) construct a knockdown-validated shRNA library targeting 520 chromatin regulators and use it to comparatively probe chromatin-associated dependencies in diverse leukemia subtypes; (2) explore the mechanistic basis of response and resistance to suppression of BRD4 and new chromatin-associated targets; and (3) pioneer a system for multiplexed combinatorial RNAi screening and use it to identify synergies between established and new chromatin-associated targets. We envision that this ERC-funded project will generate a comprehensive functional-genetic dataset that will greatly complement ongoing genome and epigenome profiling studies and ultimately guide the development of targeted therapies for leukemia and, potentially, other cancers.
Max ERC Funding
1 498 985 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
Project acronym CombaTCancer
Project Rational combination therapies for metastatic cancer
Researcher (PI) Anna Obenauf
Host Institution (HI) FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH
Call Details Starting Grant (StG), LS4, ERC-2017-STG
Summary Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Summary
Targeted therapy (TT) is frequently used to treat metastatic cancer. Although TT can achieve effective tumor control for several months, durable treatment responses are rare, due to emergence of aggressive, drug-resistant clones (RCs) with high metastatic competence. Tumor heterogeneity and plasticity result in multifaceted resistance mechanisms and targeting RCs poses a daunting challenge.
To better understand the clinical emergence of RCs, my work focuses on the poorly understood events during TT-induced tumor regression. We recently reported that during this phase drug-responsive cancer cells release a therapy-induced secretome, which remodels the tumor microenvironment (TME) and propagates disease relapse by promoting the survival of drug-sensitive cells and stimulating the outgrowth of RCs. Consequently, intervening with combination therapies during the tumor regression period has the potential to prevent the clinical emergence of RCs in the first place.
Here, we outline strategies to (1) understand how RCs emerge and (2) to leverage our findings on the TME remodeling for combination therapies. First, we will develop a novel and innovative parental clone-lookup method, that will allow us to identify and isolate treatment-naïve, parental clones (PCs) that gave rise to RCs. In functional experiments, we will assess (i) whether PCs were already resistant before or developed resistance during TT, (ii) whether PCs have a higher susceptibility to develop resistance than random clones, and (iii) the mechanistic basis for metastatic competence in different clones. Second, we will study the TT-induced TME remodeling, focusing on the effects on tumor vasculature and immune cells. We will utilize our results to target PCs and RCs by combining TT in the phase of tumor regression with other therapies, such as immunotherapies. Our study will provide new mechanistic insights into the biological processes during tumor regression and aims for novel therapeutic strategies.
Max ERC Funding
1 500 000 €
Duration
Start date: 2018-03-01, End date: 2023-02-28
Project acronym COMBINE
Project From flies to humans combining whole genome screens and tissue specific gene targeting to identify novel pathways involved in cancer and metastases
Researcher (PI) Josef Martin Penninger
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Call Details Advanced Grant (AdG), LS4, ERC-2008-AdG
Summary Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.
Summary
Cancer care will be revolutionized over the next decade by the introduction of novel therapeutics that target the underlying molecular mechanisms of the disease. With the advent of human genetics, a plethora of genes have been correlated with human diseases such as cancer the SNP maps. Since the sequences are now available, the next big challenge is to determine the function of these genes in the context of the entire organism. Genetic animal models have proven to be extremely valuable to elucidate the essential functions of genes in normal physiology and the pathogenesis of disease. Using gene-targeted mice we have previously identified RANKL as a master gene of bone loss in arthritis, osteoporosis, and cancer cell migration and metastases and genes that control heart and kidney function; wound healing; diabetes; or lung injury Our primary goal is to use functional genomics in Drosophila and mice to understand cell transformation, invasion, and cancer metastases of epithelial tumors. The following projects are proposed: 1. Role of the key osteoclast differentiation factors RANKL-RANK and its downstream signalling cascade in the development of breast and prostate cancer. 2. Requirement of osteoclasts for bone metastases and stem cell niches using a new RANKfloxed allele; function of RANKL-RANK in local tumor cell invasion. 3. Role of RANKL-RANK in the central fever response to understand potential implications of future RANKL-RANK directed therapies. 4. Integration of gene targeting in mice with state-of-the art technologies in fly genetics; use of whole genome tissue-specific in vivo RNAi Drosophila libraries to identify essential and novel pathways for cancer pathogenesis using whole genome screens. 5. Role of TSPAN6, as a candidate lung metastasis gene. Identification of new cancer disease genes will allow us to design novel strategies for cancer treatment and will have ultimately impact on the basic understanding of cancer, metastases, and human health.
Max ERC Funding
2 499 465 €
Duration
Start date: 2009-01-01, End date: 2013-12-31
Project acronym CSI-Fun
Project Chronic Systemic Inflammation: Functional organ cross-talk in inflammatory disease and cancer
Researcher (PI) Erwin Friedrich WAGNER
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Advanced Grant (AdG), LS4, ERC-2016-ADG
Summary Chronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.
Summary
Chronic Systemic Inflammation (CSI) resulting from systemic release of inflammatory cytokines and activation of the immune system is responsible for the progression of several debilitating diseases, such as Psoriasis, Arthritis and Cancer. Initially localised diseases can result in CSI with subsequent systemic spread to distant organs, a key patho-physiological phase responsible for major morbidity and even mortality. Despite the importance of CSI, a complete understanding of the molecular mechanisms, signalling pathways and cell types involved, as well as the chronological evolution of the systemic inflammatory response is still elusive. The classical approach to study inflammation has focused on investigating individual cell types or organs in the pathogenesis of a single disease, thereby neglecting important organ cross-talk and systemic interactions. Furthermore, understanding the temporal and spatial kinetics modulating the inflammatory response requires a detailed study of interactions between different immune and non-immune organs at various time points during disease progression in the context of the whole organism.
The aim of this research proposal is to substantially advance our understanding of whole organ physiology in relation to systemic inflammation as a cause or/and consequence of disease with the focus on Psoriasis/Joint Diseases and Cancer Cachexia. The goal is to elucidate the molecular mechanisms at the cellular and systemic level, and to decipher endocrine interactions and cross-talks between distant organs. Various model systems ranging from cell cultures to genetically engineered mouse models to human clinical samples will be employed. Genomic, proteomic and metabolomic data will be combined with functional in vivo assessment using mouse models to understand the multi-faceted role of systemic inflammation in chronic human diseases, such as Inflammatory Skin/Joint disease and Cachexia, a deadly systemic manifestation of Cancer.
Max ERC Funding
2 499 875 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym HAPLOID
Project “Yeast” genetics in mammalian cells to identify fundamental mechanisms of physiology and pathophysiology
Researcher (PI) Josef Penninger
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary "Some organisms such as yeast or social insects are haploid, i.e. they carry a single set of chromosomes. Organisms with a single copy of their genome provide a basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Recessive genetic screens have markedly contributed to our understanding of normal development, basic physiology, and disease. However, all somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure mutational screens. Although deemed impossible, we were able to develop generate mammalian haploid embryonic stem cells, thereby breaking a paradigm of biology.
Our novel stem opens the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. The following projects are proposed:
1. Towards“yeast” genetics in mammalian stem cells. Development of optimized technologies for rapid, genome-wide screens via repairable mutagenesis. Mutational bar-coding to introduce quantitative genomics to mammalian biology.
2. Forward genetic screens to uncover essential stem cell genes, identify novel stemness factors, develop improved systems for iPS cell derivation, and to perform synthetic lethal screens for anti-cancer drugs.
3. Reverse genetics using to identify and validate genes involved in cardiovascular physiology, brown and white fat cell development, and pain sensing.
4. Hit validation – exemplified by resistance to the bioweapon ricin.
Haploid embryonic stem cells carry the promise to revolutionize functional genetics and allow rapid, near whole genome-wide mutational forward genetics analysis and reverse genetics in defined cell types. Our systems will be made available to all researchers and the knowledge gained from our studies should fundamentally impact on the basic understanding of physiology and disease pathogenesis."
Summary
"Some organisms such as yeast or social insects are haploid, i.e. they carry a single set of chromosomes. Organisms with a single copy of their genome provide a basis for genetic analyses where any recessive mutation of essential genes will show a clear phenotype due to the absence of a second gene copy. Recessive genetic screens have markedly contributed to our understanding of normal development, basic physiology, and disease. However, all somatic mammalian cells carry two copies of chromosomes (diploidy) that obscure mutational screens. Although deemed impossible, we were able to develop generate mammalian haploid embryonic stem cells, thereby breaking a paradigm of biology.
Our novel stem opens the possibility of combining the power of a haploid genome with pluripotency of embryonic stem cells to uncover fundamental biological processes in defined cell types at a genomic scale. The following projects are proposed:
1. Towards“yeast” genetics in mammalian stem cells. Development of optimized technologies for rapid, genome-wide screens via repairable mutagenesis. Mutational bar-coding to introduce quantitative genomics to mammalian biology.
2. Forward genetic screens to uncover essential stem cell genes, identify novel stemness factors, develop improved systems for iPS cell derivation, and to perform synthetic lethal screens for anti-cancer drugs.
3. Reverse genetics using to identify and validate genes involved in cardiovascular physiology, brown and white fat cell development, and pain sensing.
4. Hit validation – exemplified by resistance to the bioweapon ricin.
Haploid embryonic stem cells carry the promise to revolutionize functional genetics and allow rapid, near whole genome-wide mutational forward genetics analysis and reverse genetics in defined cell types. Our systems will be made available to all researchers and the knowledge gained from our studies should fundamentally impact on the basic understanding of physiology and disease pathogenesis."
Max ERC Funding
2 499 951 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym LipoCheX
Project The Role of Lipolysis in the Pathogenesis of
Cancer-associated Cachexia
Researcher (PI) Rudolf Zechner
Host Institution (HI) UNIVERSITAET GRAZ
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary Cachexia is a complex syndrome characterized by massive loss of body weight due to uncontrolled loss of adipose tissue and skeletal muscle. The wasting occurs during late stages of many unrelated chronic diseases and frequently leads to the death of affected individuals. Cachexia is most common in cancer, where an estimated 25% of patients die from cancer-associated cachexia (CAC) rather than from the cancer. Despite the tremendous impact of CAC on morbidity and mortality, the underlying molecular mechanisms are poorly understood.
Recently, we demonstrated that lipase-catalyzed triacylglycerol (TG) catabolism is required for the pathogenesis of CAC. Mice lacking adipose triglyceride lipase, the rate-limiting enzyme for TG hydrolysis (lipolysis), were completely protected from loss of both adipose tissue and muscle in two forms of cancer. This implies an essential role of the lipolytic process in the pathogenesis of CAC. Here we propose to elucidate the causal role of lipases and their coregulators in CAC development. We will determine mechanisms involved and pursue novel treatment strategies.
Our objectives are to:
- Investigate how different cancers in mice regulate tissue-specific lipolysis;
- Elucidate the functional role of lipases and their coregulators in the pathogenesis of CAC;
- Assess whether pharmacological inhibition of specific lipases prevents or delays CAC;
- Study the effects of cancer-induced lipolysis on energy dissipating pathways and epigenetic control.
The project enters a largely unexplored field: the role of lipid metabolism in the pathogenesis of CAC. The work will heavily rely on the characterization of induced mutant mouse models with CAC and require extensive collaboration with experts in pathology and large-scale systems analytics. The results are expected to yield new mechanisms of disease development and provide novel therapeutic targets to prevent the devastating and prevalent consequences of CAC.
Summary
Cachexia is a complex syndrome characterized by massive loss of body weight due to uncontrolled loss of adipose tissue and skeletal muscle. The wasting occurs during late stages of many unrelated chronic diseases and frequently leads to the death of affected individuals. Cachexia is most common in cancer, where an estimated 25% of patients die from cancer-associated cachexia (CAC) rather than from the cancer. Despite the tremendous impact of CAC on morbidity and mortality, the underlying molecular mechanisms are poorly understood.
Recently, we demonstrated that lipase-catalyzed triacylglycerol (TG) catabolism is required for the pathogenesis of CAC. Mice lacking adipose triglyceride lipase, the rate-limiting enzyme for TG hydrolysis (lipolysis), were completely protected from loss of both adipose tissue and muscle in two forms of cancer. This implies an essential role of the lipolytic process in the pathogenesis of CAC. Here we propose to elucidate the causal role of lipases and their coregulators in CAC development. We will determine mechanisms involved and pursue novel treatment strategies.
Our objectives are to:
- Investigate how different cancers in mice regulate tissue-specific lipolysis;
- Elucidate the functional role of lipases and their coregulators in the pathogenesis of CAC;
- Assess whether pharmacological inhibition of specific lipases prevents or delays CAC;
- Study the effects of cancer-induced lipolysis on energy dissipating pathways and epigenetic control.
The project enters a largely unexplored field: the role of lipid metabolism in the pathogenesis of CAC. The work will heavily rely on the characterization of induced mutant mouse models with CAC and require extensive collaboration with experts in pathology and large-scale systems analytics. The results are expected to yield new mechanisms of disease development and provide novel therapeutic targets to prevent the devastating and prevalent consequences of CAC.
Max ERC Funding
2 499 446 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym POLICE
Project The PIDDosome in Centrosome and Ploidy-Surveillance
Researcher (PI) Andreas VILLUNGER
Host Institution (HI) MEDIZINISCHE UNIVERSITAT INNSBRUCK
Call Details Advanced Grant (AdG), LS4, ERC-2017-ADG
Summary Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood.
We recently demonstrated that the “PIDDosome” complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome.
This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define
(i) the relevance of the PIDDosome in aneuploidy tolerance of cancer
(ii) the role of the PIDDosome in controlling sterile inflammation and immunity
(iii) the PIDDosome as a key-regulator of organ development and regeneration
POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Summary
Tight control of the number of chromosome sets in a cell (ploidy) is fundamental for normal development and organismal health. Most cells in our body are diploid, yet, some cells, including cardiomyocytes or hepatocytes require a balanced increase in ploidy for proper function. Polyploidization is accompanied by an accumulation of centrosomes, structures needed for nucleating the mitotic spindle and ciliogenesis. Extra centrosomes, however, promote aneuploidy in proliferating cells by causing errors in chromosome segregation, underlying a series of human pathologies, most notably cancer and premature ageing. How polyploidization is controlled in organogenesis and how errors in ploidy control contribute to disease is poorly understood.
We recently demonstrated that the “PIDDosome” complex polices centrosome numbers in mammalian cells, alerting the tumor suppressor p53 in response to extra centrosomes. This is achieved by inactivating MDM2, the key-inhibitor of p53, by targeted proteolysis. MDM2-processing is mediated by caspase-2, a neglected member in a protease family that controls cell death and inflammation, activated in the PIDDosome.
This exciting finding allows examining the consequences of deregulated ploidy and centrosome number in development and disease without interfering with p53, nor the cell fusion or cytokinesis machineries. This puts us in pole position to carry out an integrative study that aims to develop the PIDDosome as a new therapeutic target in cancer, related inflammation and in regenerative medicine. To meet this aim, we will define
(i) the relevance of the PIDDosome in aneuploidy tolerance of cancer
(ii) the role of the PIDDosome in controlling sterile inflammation and immunity
(iii) the PIDDosome as a key-regulator of organ development and regeneration
POLICE will open new lines of research at the interface of cell cycle, cell death & inflammation control and promote the PIDDosome as new target in our efforts to improve human health.
Max ERC Funding
2 355 000 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym Secret-Cells
Project Cellular diversity and stress-induced cell-state switches in the mammalian hypothalamus
Researcher (PI) Tibor HARKANY
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Advanced Grant (AdG), LS4, ERC-2015-AdG
Summary The hypothalamus is an essential interface among neuroendocrine, autonomic and somatomotor systems, allowing dynamic bodily adaptations to environmental cues via the orchestration of complex physiological processes. Hypothalamic nuclei exhibit unprecedented molecular, structural and functional diversity of neurons, reflecting the breadth of neuroendocrine output. To date, a significant portion of hypothalamic neurons remains unaccounted for given the lack of identity markers. For known hypothalamic neuron subtypes, their ability to undergo stimulus-dependent expressional switches challenge their neurotransmitter- and neuropeptide-based classifications. These gaps of knowledge limit conceptual advances on neuronal loci, dynamic synapse recruitment and network hierarchy for metabolic control, and the molecular origins of disease. We have established the single cell transcriptome landscape of the paraventricular nucleus including its magno- and parvocellular domains. We will use this template to reveal novel cell identities and cell-state switches upon acute stress. We describe >25 neuronal subtypes under stress-free conditions, surpassing the resolution of any prior approach. Thus, we will resolve neurotransmitter-neuropeptide relationships at the single neuron level, with a focus on corticotropin-releasing hormone (CRH), determine biophysical parameters of CRH co-release with a fast neurotransmitter, and decipher changes to afferent organization upon stress. A novel parvocellular subclass constitutively expresses secretagogin, a calcium-sensor, which is indispensable for CRH release. We will link secretagogin loss-of-function in CRH neurons to Addison’s disease (chronic adrenal insufficiency associated with insulin resistance). Moreover, we propose a (pro-)hormone-like role for secretagogin released from CRH neurons into the circulation. Overall, our work program will produce new understanding on cellular diversity and organizational rules in the hypothalamus.
Summary
The hypothalamus is an essential interface among neuroendocrine, autonomic and somatomotor systems, allowing dynamic bodily adaptations to environmental cues via the orchestration of complex physiological processes. Hypothalamic nuclei exhibit unprecedented molecular, structural and functional diversity of neurons, reflecting the breadth of neuroendocrine output. To date, a significant portion of hypothalamic neurons remains unaccounted for given the lack of identity markers. For known hypothalamic neuron subtypes, their ability to undergo stimulus-dependent expressional switches challenge their neurotransmitter- and neuropeptide-based classifications. These gaps of knowledge limit conceptual advances on neuronal loci, dynamic synapse recruitment and network hierarchy for metabolic control, and the molecular origins of disease. We have established the single cell transcriptome landscape of the paraventricular nucleus including its magno- and parvocellular domains. We will use this template to reveal novel cell identities and cell-state switches upon acute stress. We describe >25 neuronal subtypes under stress-free conditions, surpassing the resolution of any prior approach. Thus, we will resolve neurotransmitter-neuropeptide relationships at the single neuron level, with a focus on corticotropin-releasing hormone (CRH), determine biophysical parameters of CRH co-release with a fast neurotransmitter, and decipher changes to afferent organization upon stress. A novel parvocellular subclass constitutively expresses secretagogin, a calcium-sensor, which is indispensable for CRH release. We will link secretagogin loss-of-function in CRH neurons to Addison’s disease (chronic adrenal insufficiency associated with insulin resistance). Moreover, we propose a (pro-)hormone-like role for secretagogin released from CRH neurons into the circulation. Overall, our work program will produce new understanding on cellular diversity and organizational rules in the hypothalamus.
Max ERC Funding
2 422 698 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym TNT-TUMORS
Project Therapeutic approaches to enhance innate immunity against Tumors
Researcher (PI) Maria SIBILIA
Host Institution (HI) MEDIZINISCHE UNIVERSITAET WIEN
Call Details Advanced Grant (AdG), LS4, ERC-2015-AdG
Summary 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.
Summary
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.
Max ERC Funding
2 499 646 €
Duration
Start date: 2016-09-01, End date: 2021-08-31
Project acronym Troy Stem Cells
Project Troy+ stomach stem cells in homeostasis, repair and pathogenesis
Researcher (PI) Bon-Kyoung Koo
Host Institution (HI) INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH
Call Details Starting Grant (StG), LS4, ERC-2014-STG
Summary The adult mammalian stomach can be divided into three distinct parts: From the proximal fore-stomach over the corpus to the distal pylorus. Due to constant exposure to mechanical stress and to hostile contents of the lumen, highly specialized cell types have to be constantly reproduced in order to maintain the function of the gastrointestinal tract. Recently, the applicant identified Troy+ chief cells as a novel stem cell population in the corpus epithelium. Troy+ chief cells displayed a very low proliferation rate indicating their quiescent nature compared to other known gastro-intestinal tract stem cells. Interestingly, these stem cells can actively divide upon tissue damage, suggesting distinctive statuses under conditions of homeostasis and injury.
As Troy+ stomach stem cells exhibit interconvertible characteristics i.e. quiescent and proliferative, they represent a unique model of adult stem cells with which we can study 1) the dynamics of stem cell propagation in homeostasis and regeneration and the underlying mechanism of this switch by analysing molecular and epigenetic profiles. Subsequently, by analysing mRNA expression profiles and epigenetic changes in Troy+ stem cells between homeostasis and injury repair, we will generate a list of genes with potentially interesting functions in cell fate decisions. We will therefore investigate 2) the stomach stem cell programme in homeostasis and regeneration using in vitro and in vivo functional genetics. Lastly, we will characterise 3) human stomach stem cells in normal and pathological conditions.
Here we pursue three main aims:
- Investigating Troy+ stem cell dynamics during homeostasis and injury repair
- Unmasking the stomach stem cell programme using in vitro and in vivo functional genetics
- Characterising human stomach stem cells
Summary
The adult mammalian stomach can be divided into three distinct parts: From the proximal fore-stomach over the corpus to the distal pylorus. Due to constant exposure to mechanical stress and to hostile contents of the lumen, highly specialized cell types have to be constantly reproduced in order to maintain the function of the gastrointestinal tract. Recently, the applicant identified Troy+ chief cells as a novel stem cell population in the corpus epithelium. Troy+ chief cells displayed a very low proliferation rate indicating their quiescent nature compared to other known gastro-intestinal tract stem cells. Interestingly, these stem cells can actively divide upon tissue damage, suggesting distinctive statuses under conditions of homeostasis and injury.
As Troy+ stomach stem cells exhibit interconvertible characteristics i.e. quiescent and proliferative, they represent a unique model of adult stem cells with which we can study 1) the dynamics of stem cell propagation in homeostasis and regeneration and the underlying mechanism of this switch by analysing molecular and epigenetic profiles. Subsequently, by analysing mRNA expression profiles and epigenetic changes in Troy+ stem cells between homeostasis and injury repair, we will generate a list of genes with potentially interesting functions in cell fate decisions. We will therefore investigate 2) the stomach stem cell programme in homeostasis and regeneration using in vitro and in vivo functional genetics. Lastly, we will characterise 3) human stomach stem cells in normal and pathological conditions.
Here we pursue three main aims:
- Investigating Troy+ stem cell dynamics during homeostasis and injury repair
- Unmasking the stomach stem cell programme using in vitro and in vivo functional genetics
- Characterising human stomach stem cells
Max ERC Funding
1 570 399 €
Duration
Start date: 2015-08-01, End date: 2020-07-31
