Project acronym ASSESS
Project Episodic Mass Loss in the Most Massive Stars: Key to Understanding the Explosive Early Universe
Researcher (PI) Alceste BONANOS
Host Institution (HI) NATIONAL OBSERVATORY OF ATHENS
Call Details Consolidator Grant (CoG), PE9, ERC-2017-COG
Summary Massive stars dominate their surroundings during their short lifetimes, while their explosive deaths impact the chemical evolution and spatial cohesion of their hosts. After birth, their evolution is largely dictated by their ability to remove layers of hydrogen from their envelopes. Multiple lines of evidence are pointing to violent, episodic mass-loss events being responsible for removing a large part of the massive stellar envelope, especially in low-metallicity galaxies. Episodic mass loss, however, is not understood theoretically, neither accounted for in state-of-the-art models of stellar evolution, which has far-reaching consequences for many areas of astronomy. We aim to determine whether episodic mass loss is a dominant process in the evolution of the most massive stars by conducting the first extensive, multi-wavelength survey of evolved massive stars in the nearby Universe. The project hinges on the fact that mass-losing stars form dust and are bright in the mid-infrared. We plan to (i) derive physical parameters of a large sample of dusty, evolved targets and estimate the amount of ejected mass, (ii) constrain evolutionary models, (iii) quantify the duration and frequency of episodic mass loss as a function of metallicity. The approach involves applying machine-learning algorithms to existing multi-band and time-series photometry of luminous sources in ~25 nearby galaxies. Dusty, luminous evolved massive stars will thus be automatically classified and follow-up spectroscopy will be obtained for selected targets. Atmospheric and SED modeling will yield parameters and estimates of time-dependent mass loss for ~1000 luminous stars. The emerging trend for the ubiquity of episodic mass loss, if confirmed, will be key to understanding the explosive early Universe and will have profound consequences for low-metallicity stars, reionization, and the chemical evolution of galaxies.
Summary
Massive stars dominate their surroundings during their short lifetimes, while their explosive deaths impact the chemical evolution and spatial cohesion of their hosts. After birth, their evolution is largely dictated by their ability to remove layers of hydrogen from their envelopes. Multiple lines of evidence are pointing to violent, episodic mass-loss events being responsible for removing a large part of the massive stellar envelope, especially in low-metallicity galaxies. Episodic mass loss, however, is not understood theoretically, neither accounted for in state-of-the-art models of stellar evolution, which has far-reaching consequences for many areas of astronomy. We aim to determine whether episodic mass loss is a dominant process in the evolution of the most massive stars by conducting the first extensive, multi-wavelength survey of evolved massive stars in the nearby Universe. The project hinges on the fact that mass-losing stars form dust and are bright in the mid-infrared. We plan to (i) derive physical parameters of a large sample of dusty, evolved targets and estimate the amount of ejected mass, (ii) constrain evolutionary models, (iii) quantify the duration and frequency of episodic mass loss as a function of metallicity. The approach involves applying machine-learning algorithms to existing multi-band and time-series photometry of luminous sources in ~25 nearby galaxies. Dusty, luminous evolved massive stars will thus be automatically classified and follow-up spectroscopy will be obtained for selected targets. Atmospheric and SED modeling will yield parameters and estimates of time-dependent mass loss for ~1000 luminous stars. The emerging trend for the ubiquity of episodic mass loss, if confirmed, will be key to understanding the explosive early Universe and will have profound consequences for low-metallicity stars, reionization, and the chemical evolution of galaxies.
Max ERC Funding
1 128 750 €
Duration
Start date: 2018-09-01, End date: 2023-08-31
Project acronym GENOMIA
Project Genomic Modifiers of Inherited Aortapathy
Researcher (PI) Bart Leo LOEYS
Host Institution (HI) UNIVERSITEIT ANTWERPEN
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature’s own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.
Summary
Thoracic aortic aneurysm and dissection (TAAD) is an important cause of morbidity and mortality in the western world. As 20% of all affected individuals have a positive family history, the genetic contribution to the development of TAAD is significant. Over the last decade dozens of genes were identified underlying syndromic and non-syndromic forms of TAAD. Although mutations in these disease culprits do not yet explain all cases, their identification and functional characterization were essential in deciphering three key aortic aneurysm/dissection patho-mechanisms: disturbed extracellular matrix homeostasis, dysregulated TGFbeta signaling and altered aortic smooth muscle cell contractility. Owing to the recent advent of next-generation sequencing technologies, I anticipate that the identification of additional genetic TAAD causes will remain quite straightforward in the coming years. Importantly, in many syndromic and non-syndromic families, significant non-penetrance and both inter- and intra-familial clinical variation are observed. So, although the primary genetic underlying mutation is identical in all these family members, the clinical spectrum varies widely from completely asymptomatic to sudden death due to aortic dissection at young age. The precise mechanisms underlying this variability remain largely elusive. Consequently, a better understanding of the functional effects of the primary mutation is highly needed and the identification of genetic variation that modifies these effects is becoming increasingly important. In this project, I carefully selected four different innovative strategies to discover mother nature’s own modifying capabilities in human and mouse aortopathy. The identification of these genetic modifiers will advance the knowledge significantly beyond the current understanding, individualize current treatment protocols to deliver true precision medicine and offer promising new leads to novel therapeutic strategies.
Max ERC Funding
1 987 860 €
Duration
Start date: 2019-01-01, End date: 2023-12-31
Project acronym ImmunoFit
Project Harnessing tumor metabolism to overcome immunosupression
Researcher (PI) Massimiliano MAZZONE
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Anti-cancer immunotherapy has provided patients with a promising treatment. Yet, it has also unveiled that the immunosuppressive tumor microenvironment (TME) hampers the efficiency of this therapeutic option and limits its success. The concept that metabolism is able to shape the immune response has gained general acceptance. Nonetheless, little is known on how the metabolic crosstalk between different tumor compartments contributes to the harsh TME and ultimately impairs T cell fitness within the tumor.
This proposal aims to decipher which metabolic changes in the TME impede proper anti-tumor immunity. Starting from the meta-analysis of public human datasets, corroborated by metabolomics and transcriptomics data from several mouse tumors, we ranked clinically relevant and altered metabolic pathways that correlate with resistance to immunotherapy. Using a CRISPR/Cas9 platform for their functional in vivo selection, we want to identify cancer cell intrinsic metabolic mediators and, indirectly, distinguish those belonging specifically to the stroma. By means of genetic tools and small molecules, we will modify promising metabolic pathways in cancer cells and stromal cells (particularly in tumor-associated macrophages) to harness tumor immunosuppression. In a mirroring approach, we will apply a similar screening tool on cytotoxic T cells to identify metabolic targets that enhance their fitness under adverse growth conditions. This will allow us to manipulate T cells ex vivo and to therapeutically intervene via adoptive T cell transfer. By analyzing the metabolic network and crosstalk within the tumor, this project will shed light on how metabolism contributes to the immunosuppressive TME and T cell maladaptation. The overall goal is to identify druggable metabolic targets that i) reinforce the intrinsic anti-tumor immune response by breaking immunosuppression and ii) promote T cell function in immunotherapeutic settings by rewiring either the TME or the T cell itself.
Summary
Anti-cancer immunotherapy has provided patients with a promising treatment. Yet, it has also unveiled that the immunosuppressive tumor microenvironment (TME) hampers the efficiency of this therapeutic option and limits its success. The concept that metabolism is able to shape the immune response has gained general acceptance. Nonetheless, little is known on how the metabolic crosstalk between different tumor compartments contributes to the harsh TME and ultimately impairs T cell fitness within the tumor.
This proposal aims to decipher which metabolic changes in the TME impede proper anti-tumor immunity. Starting from the meta-analysis of public human datasets, corroborated by metabolomics and transcriptomics data from several mouse tumors, we ranked clinically relevant and altered metabolic pathways that correlate with resistance to immunotherapy. Using a CRISPR/Cas9 platform for their functional in vivo selection, we want to identify cancer cell intrinsic metabolic mediators and, indirectly, distinguish those belonging specifically to the stroma. By means of genetic tools and small molecules, we will modify promising metabolic pathways in cancer cells and stromal cells (particularly in tumor-associated macrophages) to harness tumor immunosuppression. In a mirroring approach, we will apply a similar screening tool on cytotoxic T cells to identify metabolic targets that enhance their fitness under adverse growth conditions. This will allow us to manipulate T cells ex vivo and to therapeutically intervene via adoptive T cell transfer. By analyzing the metabolic network and crosstalk within the tumor, this project will shed light on how metabolism contributes to the immunosuppressive TME and T cell maladaptation. The overall goal is to identify druggable metabolic targets that i) reinforce the intrinsic anti-tumor immune response by breaking immunosuppression and ii) promote T cell function in immunotherapeutic settings by rewiring either the TME or the T cell itself.
Max ERC Funding
1 999 721 €
Duration
Start date: 2018-07-01, End date: 2023-06-30
Project acronym MetaRegulation
Project Metabolic regulation of metastatic growth
Researcher (PI) Sarah-Maria FENDT
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Metastatic growth of cancer cells requires extracellular matrix (ECM) production. The current understanding is that transcription factors regulate ECM production and thus metastatic growth by increasing the expression of collagen prolyl 4-hydroxylase (CP4H). In contrast, we recently discovered that metabolism regulates CP4H activity independently of the known transcription factors. Specifically, we found that loss of pyruvate metabolism inhibits CP4H activity and consequently ECM–dependent breast cancer cell growth. Based on this discovery we propose the novel concept that metabolism regulates metastatic growth by increasing ECM production.
In this project we will investigate the following questions: 1) What is the mechanism by which pyruvate regulates CP4H activity in breast cancer cells? To address this question we will investigate pyruvate metabolism and ECM production in 3D cultures of various breast cancer cell lines using 13C tracer analysis, metabolomics, and two-photon microscopy based ECM visualization. 2) How can this novel metabolic regulation be exploited to inhibit breast cancer-derived lung metastases growth? To address this question we will inhibit pyruvate metabolism in metastatic breast cancer mouse models using genetically modified cells and small molecules in combination with immuno- and chemotherapy. 3) How can this novel regulation be translated to different metastatic sites and cancers of different origin? To address this question we will determine the in vivo metabolism of breast cancer-, lung cancer-, and melanoma-derived liver and lung metastases (using metabolomics and 13C tracer analysis), and link it to ECM production (using two-photon microscopy based ECM visualization).
With this project we will deliver a novel concept by which metabolism regulates metastatic growth. In a long-term perspective we expect that targeting this novel metabolic regulation will pave the way for an unexplored approach to treat cancer metastases.
Summary
Metastatic growth of cancer cells requires extracellular matrix (ECM) production. The current understanding is that transcription factors regulate ECM production and thus metastatic growth by increasing the expression of collagen prolyl 4-hydroxylase (CP4H). In contrast, we recently discovered that metabolism regulates CP4H activity independently of the known transcription factors. Specifically, we found that loss of pyruvate metabolism inhibits CP4H activity and consequently ECM–dependent breast cancer cell growth. Based on this discovery we propose the novel concept that metabolism regulates metastatic growth by increasing ECM production.
In this project we will investigate the following questions: 1) What is the mechanism by which pyruvate regulates CP4H activity in breast cancer cells? To address this question we will investigate pyruvate metabolism and ECM production in 3D cultures of various breast cancer cell lines using 13C tracer analysis, metabolomics, and two-photon microscopy based ECM visualization. 2) How can this novel metabolic regulation be exploited to inhibit breast cancer-derived lung metastases growth? To address this question we will inhibit pyruvate metabolism in metastatic breast cancer mouse models using genetically modified cells and small molecules in combination with immuno- and chemotherapy. 3) How can this novel regulation be translated to different metastatic sites and cancers of different origin? To address this question we will determine the in vivo metabolism of breast cancer-, lung cancer-, and melanoma-derived liver and lung metastases (using metabolomics and 13C tracer analysis), and link it to ECM production (using two-photon microscopy based ECM visualization).
With this project we will deliver a novel concept by which metabolism regulates metastatic growth. In a long-term perspective we expect that targeting this novel metabolic regulation will pave the way for an unexplored approach to treat cancer metastases.
Max ERC Funding
2 000 000 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym MULTIPLES
Project The MULTIPLicity of supErnova progenitorS
Researcher (PI) Hugues Albert SANA
Host Institution (HI) KATHOLIEKE UNIVERSITEIT LEUVEN
Call Details Consolidator Grant (CoG), PE9, ERC-2017-COG
Summary With stellar masses in the range of eight to several hundreds of solar masses, massive stars are among the most important cosmic engines, each individual object strongly impacting its local environment and populations of massive stars driving the evolution of galaxies throughout the history of the universe. Recently, I have shown that stars more massive than 15 Msun rarely, if at all, form and live in isolation but rather as part of a binary or higher-order multiple system. Understanding the life cycle of massive multiple systems, from their birth to their death as supernovae and long-duration gamma ray bursts, is one of the most pressing scientific questions in modern astrophysics.
To obtain the key observational breakthroughs needed to revolutionize our understanding of high-mass stars, my research program is developed along three themes:
(i) investigate the physical processes that set the multiplicity properties of massive stars,
(ii) establish the multiplicity properties of unevolved massive stars across the entire mass range,
(iii) identify and uniquely characterize post-interaction products.
The implementation of the MULTIPLES program involves ambitious time-resolved observational campaigns targeting large populations of massive stars at key stages of their pre-supernova evolution and in different metallicity environments. These campaigns will combine state-of-the-art spectroscopy and high-angular resolution techniques with novel multiplicity and atmosphere analysis methods appropriate for multiple systems. Upon completion, the observational constraints that will be obtained in this project will have implications that extend well beyond the sole domain of stellar astrophysics.
Summary
With stellar masses in the range of eight to several hundreds of solar masses, massive stars are among the most important cosmic engines, each individual object strongly impacting its local environment and populations of massive stars driving the evolution of galaxies throughout the history of the universe. Recently, I have shown that stars more massive than 15 Msun rarely, if at all, form and live in isolation but rather as part of a binary or higher-order multiple system. Understanding the life cycle of massive multiple systems, from their birth to their death as supernovae and long-duration gamma ray bursts, is one of the most pressing scientific questions in modern astrophysics.
To obtain the key observational breakthroughs needed to revolutionize our understanding of high-mass stars, my research program is developed along three themes:
(i) investigate the physical processes that set the multiplicity properties of massive stars,
(ii) establish the multiplicity properties of unevolved massive stars across the entire mass range,
(iii) identify and uniquely characterize post-interaction products.
The implementation of the MULTIPLES program involves ambitious time-resolved observational campaigns targeting large populations of massive stars at key stages of their pre-supernova evolution and in different metallicity environments. These campaigns will combine state-of-the-art spectroscopy and high-angular resolution techniques with novel multiplicity and atmosphere analysis methods appropriate for multiple systems. Upon completion, the observational constraints that will be obtained in this project will have implications that extend well beyond the sole domain of stellar astrophysics.
Max ERC Funding
1 991 243 €
Duration
Start date: 2018-10-01, End date: 2023-09-30
Project acronym NoMePaCa
Project Novel Metabolic Pathways in Cancer
Researcher (PI) Guido BOMMER
Host Institution (HI) UNIVERSITE CATHOLIQUE DE LOUVAIN
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary Metabolic adaptations in central carbon metabolism play a key role in cancer. Yet, the success of therapeutic interventions in major pathways has been limited, although some of the changes have been known to exist for almost 100 years.
Biochemical textbooks present intermediary metabolism as something canonical, and the molecular identity of most enzymes required for the production of known intermediary metabolites is indeed known. Yet, the function of many putative enzymes is still unknown, indicating that novel metabolic pathways containing so far unknown metabolites exist.
We have recently discovered a novel metabolic pathway containing two metabolites that have never been described before. Preliminary data indicate that this pathway might play an important role in a group of cancers sharing specific mutations. Furthermore, genetic inactivation of a component of this pathway in mice is compatible with normal development, indicating that pharmacological inhibition should be well tolerated.
In the present project, we will use a multi-dimensional approach combining biochemical, genetic and pharmacological techniques, to identify missing components of this metabolic pathway and assess its role in cellular metabolism and cancer development. In the process of this, we will develop tools that will allow us to test whether this pathway can be targeted in vivo. Thus, our work will lead to the description of a novel metabolic pathway, should reveal novel regulatory circuits and might open novel therapeutic avenues in cancer and beyond.
Summary
Metabolic adaptations in central carbon metabolism play a key role in cancer. Yet, the success of therapeutic interventions in major pathways has been limited, although some of the changes have been known to exist for almost 100 years.
Biochemical textbooks present intermediary metabolism as something canonical, and the molecular identity of most enzymes required for the production of known intermediary metabolites is indeed known. Yet, the function of many putative enzymes is still unknown, indicating that novel metabolic pathways containing so far unknown metabolites exist.
We have recently discovered a novel metabolic pathway containing two metabolites that have never been described before. Preliminary data indicate that this pathway might play an important role in a group of cancers sharing specific mutations. Furthermore, genetic inactivation of a component of this pathway in mice is compatible with normal development, indicating that pharmacological inhibition should be well tolerated.
In the present project, we will use a multi-dimensional approach combining biochemical, genetic and pharmacological techniques, to identify missing components of this metabolic pathway and assess its role in cellular metabolism and cancer development. In the process of this, we will develop tools that will allow us to test whether this pathway can be targeted in vivo. Thus, our work will lead to the description of a novel metabolic pathway, should reveal novel regulatory circuits and might open novel therapeutic avenues in cancer and beyond.
Max ERC Funding
1 989 103 €
Duration
Start date: 2018-05-01, End date: 2023-04-30
Project acronym PASIPHAE
Project Overcoming the Dominant Foreground of Inflationary B-modes: Tomography of Galactic Magnetic Dust via Measurements of Starlight Polarization
Researcher (PI) Konstantinos TASSIS
Host Institution (HI) IDRYMA TECHNOLOGIAS KAI EREVNAS
Call Details Consolidator Grant (CoG), PE9, ERC-2017-COG
Summary An inflation-probing B-mode signal in the polarization of the cosmic microwave background (CMB) would be a discovery of utmost importance in physics. While such a signal is aggressively pursued by experiments around the world, recent Planck results have showed that this breakthrough is still out of reach, because of contamination from Galactic dust. To get to the primordial B-modes, we need to subtract polarized emission of magnetized interstellar dust with high accuracy. A critical piece of this puzzle is the 3D structure of the magnetic field threading dust clouds, which cannot be accessed through microwave observations alone, since they record integrated emission along the line of sight. Instead, observations of a large number of stars at known distances in optical polarization, tracing the same CMB-obscuring dust, can map the magnetic field between them. The Gaia mission is measuring distances to a billion stars, providing an opportunity to produce, the first-ever tomographic map of the Galactic magnetic field, using optical polarization of starlight. Such a map would not only boost CMB polarization foreground removal, but it would also have a profound impact in a wide range of astrophysical research, including interstellar medium physics, high-energy astrophysics, and galactic evolution. Taking advantage of our privately-funded, novel-technology, high-accuracy WALOP optopolarimeters currently under construction, we propose an ambitious optopolarimetric program of unprecedented scale that can meet this challenge: a survey of both northern and southern Galactic polar regions targeted by CMB experiments, covering >10,000 square degrees, which will measure linear optical polarization at 0.2% accuracy of over 360 stars per square degree (over 3.5M stars, a 1000-fold increase over the state of the art), combining wide-field-optimized instruments and an extraordinary commitment of observing time by Skinakas Observatory and the South African Astronomical Observatory.
Summary
An inflation-probing B-mode signal in the polarization of the cosmic microwave background (CMB) would be a discovery of utmost importance in physics. While such a signal is aggressively pursued by experiments around the world, recent Planck results have showed that this breakthrough is still out of reach, because of contamination from Galactic dust. To get to the primordial B-modes, we need to subtract polarized emission of magnetized interstellar dust with high accuracy. A critical piece of this puzzle is the 3D structure of the magnetic field threading dust clouds, which cannot be accessed through microwave observations alone, since they record integrated emission along the line of sight. Instead, observations of a large number of stars at known distances in optical polarization, tracing the same CMB-obscuring dust, can map the magnetic field between them. The Gaia mission is measuring distances to a billion stars, providing an opportunity to produce, the first-ever tomographic map of the Galactic magnetic field, using optical polarization of starlight. Such a map would not only boost CMB polarization foreground removal, but it would also have a profound impact in a wide range of astrophysical research, including interstellar medium physics, high-energy astrophysics, and galactic evolution. Taking advantage of our privately-funded, novel-technology, high-accuracy WALOP optopolarimeters currently under construction, we propose an ambitious optopolarimetric program of unprecedented scale that can meet this challenge: a survey of both northern and southern Galactic polar regions targeted by CMB experiments, covering >10,000 square degrees, which will measure linear optical polarization at 0.2% accuracy of over 360 stars per square degree (over 3.5M stars, a 1000-fold increase over the state of the art), combining wide-field-optimized instruments and an extraordinary commitment of observing time by Skinakas Observatory and the South African Astronomical Observatory.
Max ERC Funding
1 887 500 €
Duration
Start date: 2018-06-01, End date: 2023-05-31
Project acronym UB-RASDisease
Project The ubiquitin system in RAS-driven disease
Researcher (PI) Anna SABLINA
Host Institution (HI) VIB
Call Details Consolidator Grant (CoG), LS4, ERC-2017-COG
Summary The RAS pathway is the most frequently activated signaling node in human disease. Despite intensive efforts, effective therapeutic strategies for RAS-driven disease remain daunting. Elucidation of the mechanisms of RAS activation promises to lead toward novel therapeutic approaches to inhibit RAS activity, and may permit identification of patients who might benefit from RAS pathway inhibitors. Our preliminary studies show that reversible ubiquitylation controls RAS activity by altering its interaction network, thus representing a conceptually novel mechanism of RAS regulation. Our initial steps towards the understanding of the RAS ubiquitylation machinery have shown that positive regulators of RAS ubiquitylation are frequently mutated or down-regulated in RAS-driven diseases, whereas negative regulators are commonly up-regulated. These striking initial results suggest that dysregulation of RAS ubiquitylation may be an alternative mechanism that drives RAS activation in human disease.
Here, we aim to elucidate the role of the ubiquitin system in RAS-driven disease. We will unravel the molecular machinery controlling RAS ubiquitylation and ascertain alterations of the identified machinery in RAS-driven disease. To assess the functional impact of these alterations, we will create genetically modified mouse models and CRISPR-engineered human cell models. We will employ cutting-edge proteomic approaches to determine how disease-associated dysregulation of RAS ubiquitylation perturbs RAS interactions and signalling. Using a synthetic biologic approach, we will obtain insights into mechanisms by which ubiquitylation modulates RAS interactions. It is significant that, in contrast to the majority of known RAS regulators, the ubiquitin enzymes are “druggable”, which implicates them as promising targets for inhibiting RAS activity. Thus, our studies could lead to new ways of defeating RAS-driven disease.
Summary
The RAS pathway is the most frequently activated signaling node in human disease. Despite intensive efforts, effective therapeutic strategies for RAS-driven disease remain daunting. Elucidation of the mechanisms of RAS activation promises to lead toward novel therapeutic approaches to inhibit RAS activity, and may permit identification of patients who might benefit from RAS pathway inhibitors. Our preliminary studies show that reversible ubiquitylation controls RAS activity by altering its interaction network, thus representing a conceptually novel mechanism of RAS regulation. Our initial steps towards the understanding of the RAS ubiquitylation machinery have shown that positive regulators of RAS ubiquitylation are frequently mutated or down-regulated in RAS-driven diseases, whereas negative regulators are commonly up-regulated. These striking initial results suggest that dysregulation of RAS ubiquitylation may be an alternative mechanism that drives RAS activation in human disease.
Here, we aim to elucidate the role of the ubiquitin system in RAS-driven disease. We will unravel the molecular machinery controlling RAS ubiquitylation and ascertain alterations of the identified machinery in RAS-driven disease. To assess the functional impact of these alterations, we will create genetically modified mouse models and CRISPR-engineered human cell models. We will employ cutting-edge proteomic approaches to determine how disease-associated dysregulation of RAS ubiquitylation perturbs RAS interactions and signalling. Using a synthetic biologic approach, we will obtain insights into mechanisms by which ubiquitylation modulates RAS interactions. It is significant that, in contrast to the majority of known RAS regulators, the ubiquitin enzymes are “druggable”, which implicates them as promising targets for inhibiting RAS activity. Thus, our studies could lead to new ways of defeating RAS-driven disease.
Max ERC Funding
1 999 796 €
Duration
Start date: 2018-04-01, End date: 2023-03-31
