Project acronym WHOLENICHE
Project Hold it or let it go: a niche decision on cancer growth
Researcher (PI) Ilaria MALANCHI
Host Institution (HI) THE FRANCIS CRICK INSTITUTE LIMITED
Call Details Consolidator Grant (CoG), LS4, ERC-2016-COG
Summary The tumour microenvironment or niche is the vital non-cancerous compartment of the tumour structure. Thus, targeting its tissue-derived cells represents a promising avenue to better therapeutic interventions. However, knowledge about the tissue cells taking part of the tumour niche during early cancer development and later progression is lagging behind due to the difficulty of analysing and following early tissue changes in the surrounding of cancer cells in vivo. In our research proposal we will use a combination of original tools developed in the lab and state of the art technologies to overcome some of these constraints and expand our understanding of which cells in the niche support early cancer cell growth. We also aim to reveal their mechanism of action and identify approaches to block the niche supportive activity. Our five-year plan has three main objectives (I, II, III), which we will meet using two original strategies. With the first strategy we will visualize the early tumourigenic niche in vivo. This will allow us (I) to identify and characterize novel cellular components during dynamic niche evolution both in the context of metastatic colonization as well as during primary tumour onset. We will also use this original approach (II) to deepen our understanding of neutrophils in cancer, a particularly crucial emerging component of the cancer niche, whose role is still debated.
After dissemination, cancer cells may encounter an unfavourable niche, failing to start colonization and remaining dormant within the tissue. However, the quiescent-permissive tissue can change, cancer cells reactivate and form metastases even a long period after tumour resection. Little is known about the changes in the niche of dormant cells capable of triggering their reactivation. With the second strategy we will generate an in vivo a controllable, dormant-permissive tissue (III) to screen for potential signals triggering dormant cells reactivation.
Summary
The tumour microenvironment or niche is the vital non-cancerous compartment of the tumour structure. Thus, targeting its tissue-derived cells represents a promising avenue to better therapeutic interventions. However, knowledge about the tissue cells taking part of the tumour niche during early cancer development and later progression is lagging behind due to the difficulty of analysing and following early tissue changes in the surrounding of cancer cells in vivo. In our research proposal we will use a combination of original tools developed in the lab and state of the art technologies to overcome some of these constraints and expand our understanding of which cells in the niche support early cancer cell growth. We also aim to reveal their mechanism of action and identify approaches to block the niche supportive activity. Our five-year plan has three main objectives (I, II, III), which we will meet using two original strategies. With the first strategy we will visualize the early tumourigenic niche in vivo. This will allow us (I) to identify and characterize novel cellular components during dynamic niche evolution both in the context of metastatic colonization as well as during primary tumour onset. We will also use this original approach (II) to deepen our understanding of neutrophils in cancer, a particularly crucial emerging component of the cancer niche, whose role is still debated.
After dissemination, cancer cells may encounter an unfavourable niche, failing to start colonization and remaining dormant within the tissue. However, the quiescent-permissive tissue can change, cancer cells reactivate and form metastases even a long period after tumour resection. Little is known about the changes in the niche of dormant cells capable of triggering their reactivation. With the second strategy we will generate an in vivo a controllable, dormant-permissive tissue (III) to screen for potential signals triggering dormant cells reactivation.
Max ERC Funding
2 000 000 €
Duration
Start date: 2017-04-01, End date: 2022-03-31
Project acronym WNT FOR BRAIN
Project Transcriptional regulation of endothelial blood brain barrier differentiation by Wnt signaling
Researcher (PI) Elisabetta Dejana
Host Institution (HI) IFOM FONDAZIONE ISTITUTO FIRC DI ONCOLOGIA MOLECOLARE
Call Details Advanced Grant (AdG), LS4, ERC-2010-AdG_20100317
Summary The brain vasculature has evolved to protect the central nervous system from the constantly changing milieu in the blood stream. Endothelial cells of brain capillaries form the so called blood brain barrier (BBB), an active permeability barrier and transport system which allows a selective passage of nutrients from blood to the nervous tissue. The continuous cross talk of endothelial cells, pericytes and nervous cells influences many vascular functions and determines and maintains the BBB characteristics after birth. Our limited knowledge of the nature of these signals prevents effective therapy of several diseases such as hemorrhagic stroke or brain edema. Furthermore, the development of tools to reversibly ¿open¿ the barrier would strongly improve drug delivery to the brain.
In the present project we propose to tackle the problem by studying the transcriptional mechanisms which direct BBB differentiation. This strategy is based on preliminary work which shows that the cross talk between nervous cells and the endothelium is mediated by Wnt factors and downstream beta-catenin transcriptional activity. The understanding of the mechanism of action of Wnt signaling on brain endothelium may yield novel strategies and tools for modulating BBB permeability.
The project is divided in three related objectives: 1) to define the mechanism of action and downstream partners of Wnt in brain angiogenesis and BBB differentiation; 2) to use this knowledge to develop an optimized BBB model in vitro and in vivo; 3) to test whether modulation of Wnt signaling may have a therapeutic impact in the regulation of BBB in pathological conditions.
Summary
The brain vasculature has evolved to protect the central nervous system from the constantly changing milieu in the blood stream. Endothelial cells of brain capillaries form the so called blood brain barrier (BBB), an active permeability barrier and transport system which allows a selective passage of nutrients from blood to the nervous tissue. The continuous cross talk of endothelial cells, pericytes and nervous cells influences many vascular functions and determines and maintains the BBB characteristics after birth. Our limited knowledge of the nature of these signals prevents effective therapy of several diseases such as hemorrhagic stroke or brain edema. Furthermore, the development of tools to reversibly ¿open¿ the barrier would strongly improve drug delivery to the brain.
In the present project we propose to tackle the problem by studying the transcriptional mechanisms which direct BBB differentiation. This strategy is based on preliminary work which shows that the cross talk between nervous cells and the endothelium is mediated by Wnt factors and downstream beta-catenin transcriptional activity. The understanding of the mechanism of action of Wnt signaling on brain endothelium may yield novel strategies and tools for modulating BBB permeability.
The project is divided in three related objectives: 1) to define the mechanism of action and downstream partners of Wnt in brain angiogenesis and BBB differentiation; 2) to use this knowledge to develop an optimized BBB model in vitro and in vivo; 3) to test whether modulation of Wnt signaling may have a therapeutic impact in the regulation of BBB in pathological conditions.
Max ERC Funding
2 390 200 €
Duration
Start date: 2011-08-01, End date: 2016-07-31
Project acronym WTBLDOHRNCE
Project Walking the tightrope between life and death: Oxygen homeostasis regulation in the nematode Caenorhabditis elegans
Researcher (PI) Einav Gross
Host Institution (HI) THE HEBREW UNIVERSITY OF JERUSALEM
Call Details Starting Grant (StG), LS4, ERC-2011-StG_20101109
Summary Oxygen (O2) is vital for the life of all aerobic animals. However, fine-tuned regulation of O2 levels is crucial since both shortage (hypoxia) and excess (via the production of reactive oxygen species, ROS) may be harmful. Indeed, both hypoxia and ROS may underlie the pathophysiology of many diseases such as atherosclerosis and Alzheimer’s. To understand how this fine-tuned O2 regulation is achieved at both the molecular and organismal levels my research proposal aims to explore the following integrated questions, using the nematode C. elegans as a model organism.
1) How do animal sense O2? What are the molecular sensors and how do they act together to fine-tune O2 responses?
2) How does O2 regulate food intake, and repress appetite in hypoxia?
3) How do animals survive and behaviorally adapt to hypoxia without HIF-1?
4) How hydrogen sulfide (H2S) regulates O2 responses and aging?
5) How do animals protect against mRNA oxidation damage?
I have focused my research on the globins. GLB-5 is a C. elegans hexacoordinated globin that regulates foraging behavior in response to subtle changes in O2 concentration. Like neuroglobin and cytoglobin in our brain, GLB-5 is expressed in neurons. Recently I discovered that GLB-5 regulates the re-adaptation of animals to 21% O2 after hypoxia. To understand how GLB-5 regulates hypoxia-reoxygenation responses I made a mutagenesis screen and isolated four classes of GLB-5 suppressors, and mapped them using single-nucleotide polymorphisms (SNP’s) to about a 1 Mbp genomic interval. Using a novel non-PCR based libraries preparation and Next Generation whole-genome sequencing, I have already sequenced four independent mutations and cloned one of the GLB-5 suppressors. In the future, I intend to clone more suppressor genes, and use this methodology in other parts of my project. By doing so, I aim to understand O2 homeostasis regulation at all levels; from the molecular signaling network to the physiology and behavior of the whole animal.
Summary
Oxygen (O2) is vital for the life of all aerobic animals. However, fine-tuned regulation of O2 levels is crucial since both shortage (hypoxia) and excess (via the production of reactive oxygen species, ROS) may be harmful. Indeed, both hypoxia and ROS may underlie the pathophysiology of many diseases such as atherosclerosis and Alzheimer’s. To understand how this fine-tuned O2 regulation is achieved at both the molecular and organismal levels my research proposal aims to explore the following integrated questions, using the nematode C. elegans as a model organism.
1) How do animal sense O2? What are the molecular sensors and how do they act together to fine-tune O2 responses?
2) How does O2 regulate food intake, and repress appetite in hypoxia?
3) How do animals survive and behaviorally adapt to hypoxia without HIF-1?
4) How hydrogen sulfide (H2S) regulates O2 responses and aging?
5) How do animals protect against mRNA oxidation damage?
I have focused my research on the globins. GLB-5 is a C. elegans hexacoordinated globin that regulates foraging behavior in response to subtle changes in O2 concentration. Like neuroglobin and cytoglobin in our brain, GLB-5 is expressed in neurons. Recently I discovered that GLB-5 regulates the re-adaptation of animals to 21% O2 after hypoxia. To understand how GLB-5 regulates hypoxia-reoxygenation responses I made a mutagenesis screen and isolated four classes of GLB-5 suppressors, and mapped them using single-nucleotide polymorphisms (SNP’s) to about a 1 Mbp genomic interval. Using a novel non-PCR based libraries preparation and Next Generation whole-genome sequencing, I have already sequenced four independent mutations and cloned one of the GLB-5 suppressors. In the future, I intend to clone more suppressor genes, and use this methodology in other parts of my project. By doing so, I aim to understand O2 homeostasis regulation at all levels; from the molecular signaling network to the physiology and behavior of the whole animal.
Max ERC Funding
1 495 922 €
Duration
Start date: 2011-11-01, End date: 2017-10-31
Project acronym YOUNGatHEART
Project YOUNGatHEART: CARDIAC REJUVENATION BY EPIGENETIC REMODELLING
Researcher (PI) SUSANA Gonzalez
Host Institution (HI) CENTRO NACIONAL DE INVESTIGACIONESCARDIOVASCULARES CARLOS III (F.S.P.)
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Aging poses the largest risk for cardiovascular disease (CVD) and is orchestrated, to some extent, by epigenetic changes. Despite the significant progress on many fronts in the cardiovascular field, non-inherited epigenetic regulation in cardiac aging and CVD remains unexplored. Dilated Cardiomyopathy (DCM) is a major contributor to healthcare costs and it is the leading indication for heart transplantation. We have recently discovered that adult cardiac-specific deletion of epigenetic regulator Bmi1 in mice induces DCM and heart failure. These unprecedented data support the idea that inadequate epigenetic regulation in adulthood is critical in CVD. In addition, our studies with parabiotic pairing of healthy and DCM-diagnosed mice show that the circulation of a healthy mouse significantly improve the cardiac performance of mouse with DCM. These ground-breaking discoveries suggest that DCM regression, or cardiac rejuvenation, is feasible in terms of epigenetic states. Therefore, YOUNGatHEART will unveil significant breakthrough on (1) how non-inherited epigenetic deregulation induces DCM and (2) how epigenetic remodeling reversed this process. For that, our challenges are: 1A. To decipher how aged-linked cardiac dysfunction contributes to CVD by identifying the epigenetic landscape regulating cardiac aging among species; 1B. To decode how epigenetic deregulation induces DCM by integrating clinical data and samples from DCM-transplanted patients with imaging, transcriptomic, proteomic, and functional approaches from DCM model; and, 2A. To identified systemic factors with anti-cardiomyopathic effects by systematic proteomic screenings after parabiosis and epigenome of the DCM hearts. In sum, YOUNGatHEART puts forward an ambitious but feasible and pioneering program to tackle the epigenetic hallmark in cardiac aging with the final aim (2B) of setting the molecular basis for future therapeutic interventions in CVD.
Summary
Aging poses the largest risk for cardiovascular disease (CVD) and is orchestrated, to some extent, by epigenetic changes. Despite the significant progress on many fronts in the cardiovascular field, non-inherited epigenetic regulation in cardiac aging and CVD remains unexplored. Dilated Cardiomyopathy (DCM) is a major contributor to healthcare costs and it is the leading indication for heart transplantation. We have recently discovered that adult cardiac-specific deletion of epigenetic regulator Bmi1 in mice induces DCM and heart failure. These unprecedented data support the idea that inadequate epigenetic regulation in adulthood is critical in CVD. In addition, our studies with parabiotic pairing of healthy and DCM-diagnosed mice show that the circulation of a healthy mouse significantly improve the cardiac performance of mouse with DCM. These ground-breaking discoveries suggest that DCM regression, or cardiac rejuvenation, is feasible in terms of epigenetic states. Therefore, YOUNGatHEART will unveil significant breakthrough on (1) how non-inherited epigenetic deregulation induces DCM and (2) how epigenetic remodeling reversed this process. For that, our challenges are: 1A. To decipher how aged-linked cardiac dysfunction contributes to CVD by identifying the epigenetic landscape regulating cardiac aging among species; 1B. To decode how epigenetic deregulation induces DCM by integrating clinical data and samples from DCM-transplanted patients with imaging, transcriptomic, proteomic, and functional approaches from DCM model; and, 2A. To identified systemic factors with anti-cardiomyopathic effects by systematic proteomic screenings after parabiosis and epigenome of the DCM hearts. In sum, YOUNGatHEART puts forward an ambitious but feasible and pioneering program to tackle the epigenetic hallmark in cardiac aging with the final aim (2B) of setting the molecular basis for future therapeutic interventions in CVD.
Max ERC Funding
1 861 910 €
Duration
Start date: 2015-11-01, End date: 2020-10-31
Project acronym zebraHeart
Project Novel insights into cardiac regeneration through studies in the zebrafish
Researcher (PI) Nadia Isabel Mercader Huber
Host Institution (HI) UNIVERSITAET BERN
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary Myocardial infarction (MI) leads to cardiomyocyte death and accumulation of myofibroblasts (MFs) at the site of injury, which produce large amounts of extracellular matrix (ECM), generating a scar. Initially, cardiac fibrosis protects from ventricular wall rupture, but subsequent myocardial remodelling causes heart failure, representing a leading cause of death in Europe. While MFs play a central role in cardiac fibrosis, there is confusion on their origin, a lack of specific markers and the existence of a unique MF type is debatable. Different MF might reveal distinct characteristics regarding ECM production, contractility, and autophagy, making them more or less pernicious. While in humans cardiac fibrosis is irreversible, other vertebrates have a remarkable capacity to regenerate damaged tissue. We recently established a zebrafish MI model and found that cardiac fibrosis is reversible and occurs as an intermediate step during regeneration. Here, the endogenous mechanisms of MFs and ECM regression will be explored. In addition, MF origin, types and fate will be characterized and manipulated to improve regeneration. As in mammals, cardiac injury elicits an inflammatory response in the zebrafish. The regenerative capacity of a species has been directly linked to features of its immune system, but surprisingly little is known on zebrafish leukocyte subtypes. We will study the role of macrophages and particularly analyse a subtype, which accumulates in the outer mesothelial layer of the heart, the epicardium. Epicardial derived cells play a key role as a trophic factor and progenitor cell source, and a first step towards regeneration includes the reestablishment of the epicardial layer. The zebrafish will offer a screening platform for small molecules triggering its activation. In sum, the project will increase the knowledge on the molecular and cellular basis of fibrosis regression, provide novel MF markers and identify new drugs to enhance cardiac regeneration.
Summary
Myocardial infarction (MI) leads to cardiomyocyte death and accumulation of myofibroblasts (MFs) at the site of injury, which produce large amounts of extracellular matrix (ECM), generating a scar. Initially, cardiac fibrosis protects from ventricular wall rupture, but subsequent myocardial remodelling causes heart failure, representing a leading cause of death in Europe. While MFs play a central role in cardiac fibrosis, there is confusion on their origin, a lack of specific markers and the existence of a unique MF type is debatable. Different MF might reveal distinct characteristics regarding ECM production, contractility, and autophagy, making them more or less pernicious. While in humans cardiac fibrosis is irreversible, other vertebrates have a remarkable capacity to regenerate damaged tissue. We recently established a zebrafish MI model and found that cardiac fibrosis is reversible and occurs as an intermediate step during regeneration. Here, the endogenous mechanisms of MFs and ECM regression will be explored. In addition, MF origin, types and fate will be characterized and manipulated to improve regeneration. As in mammals, cardiac injury elicits an inflammatory response in the zebrafish. The regenerative capacity of a species has been directly linked to features of its immune system, but surprisingly little is known on zebrafish leukocyte subtypes. We will study the role of macrophages and particularly analyse a subtype, which accumulates in the outer mesothelial layer of the heart, the epicardium. Epicardial derived cells play a key role as a trophic factor and progenitor cell source, and a first step towards regeneration includes the reestablishment of the epicardial layer. The zebrafish will offer a screening platform for small molecules triggering its activation. In sum, the project will increase the knowledge on the molecular and cellular basis of fibrosis regression, provide novel MF markers and identify new drugs to enhance cardiac regeneration.
Max ERC Funding
1 499 215 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym ZF-MEL-CHEMBIO
Project Chemical Biology in Zebrafish: Drug-Leads and New Targets in the Melanocyte Lineage and Melanoma
Researcher (PI) Eleanor Elizabeth Patton
Host Institution (HI) THE UNIVERSITY OF EDINBURGH
Call Details Consolidator Grant (CoG), LS4, ERC-2014-CoG
Summary Melanoma (cancer of the melanocyte) kills over 20,000 Europeans each year and incidence continues to rise rapidly. BRAF(V600E) inhibitors have led to clinically significant improvements in outcomes for melanoma patients, yet many patients with metastatic melanoma rapidly succumb to the disease due to eventual chemoresistance, or insensitivity to the drug. Thus, it is critical to identify new therapies that can act alone, or be combined with available treatments for enhanced efficacy and/or to overcome drug resistance.
An important and new therapeutic concept for melanoma is to target the melanocyte lineage. Recent evidence reveals that a melanocyte lineage specific programme maintains melanoma survival, and we have engineered the first animal model in zebrafish to demonstrate that targeting the master melanocyte lineage transcription factor MITF leads to rapid melanoma regression. Thus, understanding and targeting the melanocyte lineage is directly relevant to melanoma, and reveals therapeutically targetable processes.
Our vision is to use live-imaging of the melanocyte lineage as the basis for phenotypic chemical screens in zebrafish to find drugs/leads and identify targetable processes that might elucidate pathways for cancer therapy. Screening for targets of the melanocyte lineage is highly relevant to melanoma because melanocytes are the melanoma cell of origin, and genes that specify the melanocyte stem cells and the lineage during embryogenesis are the same genes that play fundamental roles in cancer. We will use innovative chemical-biology to capture and validate targets in vivo, and perform chemo-preventative and -therapeutic trials in zebrafish melanoma models using known and novel drug-delivery methods.
Ultimately, we aim to translate our most promising drug/leads and targets into the mammalian system, to establish the basis for patent applications and clinical trials.
Summary
Melanoma (cancer of the melanocyte) kills over 20,000 Europeans each year and incidence continues to rise rapidly. BRAF(V600E) inhibitors have led to clinically significant improvements in outcomes for melanoma patients, yet many patients with metastatic melanoma rapidly succumb to the disease due to eventual chemoresistance, or insensitivity to the drug. Thus, it is critical to identify new therapies that can act alone, or be combined with available treatments for enhanced efficacy and/or to overcome drug resistance.
An important and new therapeutic concept for melanoma is to target the melanocyte lineage. Recent evidence reveals that a melanocyte lineage specific programme maintains melanoma survival, and we have engineered the first animal model in zebrafish to demonstrate that targeting the master melanocyte lineage transcription factor MITF leads to rapid melanoma regression. Thus, understanding and targeting the melanocyte lineage is directly relevant to melanoma, and reveals therapeutically targetable processes.
Our vision is to use live-imaging of the melanocyte lineage as the basis for phenotypic chemical screens in zebrafish to find drugs/leads and identify targetable processes that might elucidate pathways for cancer therapy. Screening for targets of the melanocyte lineage is highly relevant to melanoma because melanocytes are the melanoma cell of origin, and genes that specify the melanocyte stem cells and the lineage during embryogenesis are the same genes that play fundamental roles in cancer. We will use innovative chemical-biology to capture and validate targets in vivo, and perform chemo-preventative and -therapeutic trials in zebrafish melanoma models using known and novel drug-delivery methods.
Ultimately, we aim to translate our most promising drug/leads and targets into the mammalian system, to establish the basis for patent applications and clinical trials.
Max ERC Funding
1 865 345 €
Duration
Start date: 2015-09-01, End date: 2021-08-31
