Project acronym ART
Project Aberrant RNA degradation in T-cell leukemia
Researcher (PI) Jan Cools
Host Institution (HI) VIB VZW
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary "The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia.
In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes.
This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."
Summary
"The deregulation of transcription is an important driver of leukemia development. Typically, transcription in leukemia cells is altered by the ectopic expression of transcription factors, by modulation of signaling pathways or by epigenetic changes. In addition to these factors that affect the production of RNAs, also changes in the processing of RNA (its splicing, transport and decay) may contribute to determine steady-state RNA levels in leukemia cells. Indeed, acquired mutations in various genes encoding RNA splice factors have recently been identified in myeloid leukemias and in chronic lymphocytic leukemia. In our study of T-cell acute lymphoblastic leukemia (T-ALL), we have identified mutations in RNA decay factors, including mutations in CNOT3, a protein believed to function in deadenylation of mRNA. It remains, however, unclear how mutations in RNA processing can contribute to the development of leukemia.
In this project, we aim to further characterize the mechanisms of RNA regulation in T-cell acute lymphoblastic leukemia (T-ALL) to obtain insight in the interplay between RNA generation and RNA decay and its role in leukemia development. We will study RNA decay in human T-ALL cells and mouse models of T-ALL, with the aim to identify the molecular consequences that contribute to leukemia development. We will use new technologies such as RNA-sequencing in combination with bromouridine labeling of RNA to measure RNA transcription and decay rates in a transcriptome wide manner allowing unbiased discoveries. These studies will be complemented with screens in Drosophila melanogaster using an established eye cancer model, previously also successfully used for the studies of T-ALL oncogenes.
This study will contribute to our understanding of the pathogenesis of T-ALL and may identify new targets for therapy of this leukemia. In addition, our study will provide a better understanding of how RNA processing is implicated in cancer development in general."
Max ERC Funding
1 998 300 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
Project acronym BETAIMAGE
Project An in vivo imaging approach to understand pancreatic beta-cell signal-transduction
Researcher (PI) Per-Olof Berggren
Host Institution (HI) KAROLINSKA INSTITUTET
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.
Summary
The challenge in cell physiology/pathology today is to translate in vitro findings to the living organism. We have developed a unique approach where signal-transduction can be investigated in vivo non-invasively, longitudinally at single cell resolution, using the anterior chamber of the eye as a natural body window for imaging. We will use this approach to understand how the universally important and highly complex signal Ca2+ is regulated in the pancreatic beta-cell, while localized in the vascularized and innervated islet of Langerhans, and how that affects the insulin secretory machinery in vivo. Engrafted islets in the eye take on identical innervation- and vascularization patterns as those in the pancreas and are proficient in regulating glucose homeostasis in the animal. Since the pancreatic islet constitutes a micro-organ, this imaging approach offers a seminal model system to understand Ca2+ signaling in individual cells at the organ level in real life. We will test the hypothesis that the Ca2+-signal has a key role in pancreatic beta-cell function and survival in vivo and that perturbation in the Ca2+-signal serves as a common denominator for beta-cell pathology associated with impaired glucose homeostasis and diabetes. Of special interest is how innervation impacts on Ca2+-dynamics and the integration of autocrine, paracrine and endocrine signals in fine-tuning the Ca2+-signal with regard to beta-cell function and survival. We aim to define key defects in the machinery regulating Ca2+-dynamics in association with the autoimmune reaction, inflammation and obesity eventually resulting in diabetes. Our imaging platform will be applied to clarify in vivo regulation of Ca2+-dynamics in both healthy and diabetic human beta-cells. To define novel drugable targets for treatment of diabetes, it is crucial to identify similarities and differences in the molecular machinery regulating the in vivo Ca2+-signal in the human and in the rodent beta-cell.
Max ERC Funding
2 499 590 €
Duration
Start date: 2014-03-01, End date: 2019-02-28
Project acronym BEYOND
Project METABOLIC BASIS OF NEURODEGENERATIVE DISEASE
Researcher (PI) Thomas Franz Erich Willnow
Host Institution (HI) MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary Alzheimer disease (AD) is the most common form of age-related dementia affecting millions of patients worldwide. Disturbingly, disorders of lipid and glucose metabolism emerge as major risk factors for onset and progression of neurodegeneration in the human population. Thus, an increasing life expectance combined with an observable rise in metabolic disturbances is expected to turn AD into one of the most serious health problems for future generations. Still, the molecular mechanisms whereby dysregulation of glucose and lipid homeostasis elicits noxious insults to the brain remain poorly understood. We characterized a novel class of intracellular sorting receptors, termed VPS10P domain receptors with dual roles in regulation of neuronal viability and function, but also in modulation of glucose and lipid homeostasis. Our proposal aims at elucidating an important yet poorly understood link between metabolism and neurodegeneration that converges on these receptors. Our approach is unique and novel in several ways. Thematically, our studies focus on a novel class of receptors previously not considered. Based on the receptors’ ability to act as sorting proteins, we propose faulty protein trafficking as a major unifying concept underlying neurodegenerative and metabolic disorders. Conceptually, our approach relies on the interdisciplinary effort of neuroscientists and metabolism researchers working jointly on pathophysiological pathways converging on these receptors. Through this effort, we are confident to gain important insights into the crosstalk between brain and peripheral tissues, and to elucidate pathways common to metabolic disturbances and dementia, two prevailing degenerative disorders inflicting our societies.
Summary
Alzheimer disease (AD) is the most common form of age-related dementia affecting millions of patients worldwide. Disturbingly, disorders of lipid and glucose metabolism emerge as major risk factors for onset and progression of neurodegeneration in the human population. Thus, an increasing life expectance combined with an observable rise in metabolic disturbances is expected to turn AD into one of the most serious health problems for future generations. Still, the molecular mechanisms whereby dysregulation of glucose and lipid homeostasis elicits noxious insults to the brain remain poorly understood. We characterized a novel class of intracellular sorting receptors, termed VPS10P domain receptors with dual roles in regulation of neuronal viability and function, but also in modulation of glucose and lipid homeostasis. Our proposal aims at elucidating an important yet poorly understood link between metabolism and neurodegeneration that converges on these receptors. Our approach is unique and novel in several ways. Thematically, our studies focus on a novel class of receptors previously not considered. Based on the receptors’ ability to act as sorting proteins, we propose faulty protein trafficking as a major unifying concept underlying neurodegenerative and metabolic disorders. Conceptually, our approach relies on the interdisciplinary effort of neuroscientists and metabolism researchers working jointly on pathophysiological pathways converging on these receptors. Through this effort, we are confident to gain important insights into the crosstalk between brain and peripheral tissues, and to elucidate pathways common to metabolic disturbances and dementia, two prevailing degenerative disorders inflicting our societies.
Max ERC Funding
2 415 229 €
Duration
Start date: 2014-02-01, End date: 2019-01-31
Project acronym CANCERMETAB
Project Metabolic requirements for prostate cancer cell fitness
Researcher (PI) Arkaitz Carracedo Perez
Host Institution (HI) ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOCIENCIAS
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.
Summary
The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.
Max ERC Funding
1 498 686 €
Duration
Start date: 2013-11-01, End date: 2019-10-31
Project acronym CARDIOREDOX
Project Redox sensing and signalling in cardiovascular health and disease
Researcher (PI) Philip Eaton
Host Institution (HI) KING'S COLLEGE LONDON
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary "We want to determine how oxidants are sensed and transduced into a biological effect within the cardiovascular system. The proposed work will focus on thiol-based redox sensors, defining their role in heart and blood vessel function during health and disease. Although this laboratory has studied the molecular basis of redox signaling for more than a decade, the subject is still in its relative infancy with considerable scope for major advances. Oxidant signaling remains a ‘hot topic’ with high profile studies confirming a fundamental role for redox control of protein and cellular function continuing to emerge. The molecular basis of redox sensing is the reaction of an oxidant with target proteins. This gives rise to oxidative post-translational modifications, most commonly of cysteinyl thiols, potentially altering the activity of proteins to regulate cell or tissue function. One of the reasons there are so many unanswered questions about redox sensing and signaling is the diversity of oxidant molecules produced by cells that can interact with sensor proteins to alter their function. This application is aimed at extending our knowledge of redox sensing and signalling, allowing us to define its importance in cardiovascular health and disease."
Summary
"We want to determine how oxidants are sensed and transduced into a biological effect within the cardiovascular system. The proposed work will focus on thiol-based redox sensors, defining their role in heart and blood vessel function during health and disease. Although this laboratory has studied the molecular basis of redox signaling for more than a decade, the subject is still in its relative infancy with considerable scope for major advances. Oxidant signaling remains a ‘hot topic’ with high profile studies confirming a fundamental role for redox control of protein and cellular function continuing to emerge. The molecular basis of redox sensing is the reaction of an oxidant with target proteins. This gives rise to oxidative post-translational modifications, most commonly of cysteinyl thiols, potentially altering the activity of proteins to regulate cell or tissue function. One of the reasons there are so many unanswered questions about redox sensing and signaling is the diversity of oxidant molecules produced by cells that can interact with sensor proteins to alter their function. This application is aimed at extending our knowledge of redox sensing and signalling, allowing us to define its importance in cardiovascular health and disease."
Max ERC Funding
2 255 659 €
Duration
Start date: 2013-12-01, End date: 2018-11-30
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 DEEPINSIGHT
Project Preclinical micro-endoscopy in tumors: targeting metastatic intravasation and resistance
Researcher (PI) Peter Friedl
Host Institution (HI) STICHTING KATHOLIEKE UNIVERSITEIT
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Poor prognosis of cancer results from two central progression events, (i) the intravasation of cancer cells into blood vessels which leads to metastasis to distant organs and ultimately lethal tumor overload and (ii) cancer cell survival and adaptation to metabolic stress which causes resistance to anti-cancer therapy and limits life expectancy. Using a novel multiphoton microendoscope device recently developed by myself and collaborators, I here aim to overcome tissue penetration limits and identify important progression events deeply inside tumors. The hard- and software of the microendoscope will be optimized for automated position control and panoramic rotation to sample large tissue volumes and validated for stability and safety. We then will address the locations and mechanisms inside tumors that: (1) enable tumor-cell migration and penetration into blood vessels for distant metastasis and (2) mediate enhanced tumor-cell survival and resistance to experimental radiation- and chemotherapy. This basic inventory will serve to address (3) whether and how the niches for both intravasation and resistance overlap and connected with microenvironmental triggers, including defective blood vessels, signalling pathways of malnutrition and hypoxia, and tissue damage. The strategies include 3D microscopy of live fluorescent multi-color tumors and molecular reporters to record cancer cell migration, proliferation and death in the context with embedding tissue structures and metabolic signals. Once identified and characterized, (4) the niches and signals inducing intravasation and resistance (i.e. integrin adhesion receptors, cytoskeletal regulators, metabolic signalling) will be exploited as targets to enhance experimental radiation and chemotherapy. Preclinical microendoscopy will deliver new insight into cancer progression further contribute impulses to microendoscopy for disease monitoring in patients (“optical biopsy”).
Summary
Poor prognosis of cancer results from two central progression events, (i) the intravasation of cancer cells into blood vessels which leads to metastasis to distant organs and ultimately lethal tumor overload and (ii) cancer cell survival and adaptation to metabolic stress which causes resistance to anti-cancer therapy and limits life expectancy. Using a novel multiphoton microendoscope device recently developed by myself and collaborators, I here aim to overcome tissue penetration limits and identify important progression events deeply inside tumors. The hard- and software of the microendoscope will be optimized for automated position control and panoramic rotation to sample large tissue volumes and validated for stability and safety. We then will address the locations and mechanisms inside tumors that: (1) enable tumor-cell migration and penetration into blood vessels for distant metastasis and (2) mediate enhanced tumor-cell survival and resistance to experimental radiation- and chemotherapy. This basic inventory will serve to address (3) whether and how the niches for both intravasation and resistance overlap and connected with microenvironmental triggers, including defective blood vessels, signalling pathways of malnutrition and hypoxia, and tissue damage. The strategies include 3D microscopy of live fluorescent multi-color tumors and molecular reporters to record cancer cell migration, proliferation and death in the context with embedding tissue structures and metabolic signals. Once identified and characterized, (4) the niches and signals inducing intravasation and resistance (i.e. integrin adhesion receptors, cytoskeletal regulators, metabolic signalling) will be exploited as targets to enhance experimental radiation and chemotherapy. Preclinical microendoscopy will deliver new insight into cancer progression further contribute impulses to microendoscopy for disease monitoring in patients (“optical biopsy”).
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-12-01, End date: 2019-11-30
Project acronym DNCURE
Project Dynamic signalling networks in Diabetic Nephropathy (DN)
– New avenues to a personalized therapy.-
Researcher (PI) Tobias Georg Bruno Maria Huber
Host Institution (HI) UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Dynamic signalling networks in Diabetic Nephropathy (DN) – New avenues to a personalized therapy.-
We have developed an exquisite experimental platform that facilitates the systematic unravelling of the signalling
networks leading to (1) the initiation, (2) the progression and (3) the potential regeneration of podocytes in
DN, paving the way to novel therapeutic strategies:
(1) DN initiation: Identification of signalling cascades leading to microalbuminuria: Molecular
By combining transgenic Drosophila lines carrying secreted fluorescent proteins to monitor the barrier function
in vivo with a genome-wide siRNA screen we will establish a unique system to directly identify gene
networks contributing to microalbuminuria.
(2a) DN progression: Molecular fingerprinting of podocyte degeneration: Based on a transgenic
fluorescent mouse model, we have pioneered a highly efficient podocyte purification method from type1 and
type 2 diabetic mice allowing us to develop a precise molecular genetic, quantitative proteomic and micro
RNA fingerprint from freshly isolated podocytes from diabetic and non-diabetic mice.
(2b) DN progression: We established a proteomic approach to measure site-specific phosphorylation dynamics in
primary podocyte cultures originating from transgenic mice that are TORC1 deficient, TORC2 deficient or
TORC1 hyperactive (TSC1 KO) solely in the podocytes.
(3) Potential role of podocyte regeneration in DN: Finally, to target mechanisms that could potentially
reverse the disease process (by repopulating lost podocytes), we invented a strategy to quantitatively monitor
podocyte turnover from different stem cell niches allowing us to precisely assess and potentially
manipulating the capacity of podocyte regeneration in DN.
Summary
Dynamic signalling networks in Diabetic Nephropathy (DN) – New avenues to a personalized therapy.-
We have developed an exquisite experimental platform that facilitates the systematic unravelling of the signalling
networks leading to (1) the initiation, (2) the progression and (3) the potential regeneration of podocytes in
DN, paving the way to novel therapeutic strategies:
(1) DN initiation: Identification of signalling cascades leading to microalbuminuria: Molecular
By combining transgenic Drosophila lines carrying secreted fluorescent proteins to monitor the barrier function
in vivo with a genome-wide siRNA screen we will establish a unique system to directly identify gene
networks contributing to microalbuminuria.
(2a) DN progression: Molecular fingerprinting of podocyte degeneration: Based on a transgenic
fluorescent mouse model, we have pioneered a highly efficient podocyte purification method from type1 and
type 2 diabetic mice allowing us to develop a precise molecular genetic, quantitative proteomic and micro
RNA fingerprint from freshly isolated podocytes from diabetic and non-diabetic mice.
(2b) DN progression: We established a proteomic approach to measure site-specific phosphorylation dynamics in
primary podocyte cultures originating from transgenic mice that are TORC1 deficient, TORC2 deficient or
TORC1 hyperactive (TSC1 KO) solely in the podocytes.
(3) Potential role of podocyte regeneration in DN: Finally, to target mechanisms that could potentially
reverse the disease process (by repopulating lost podocytes), we invented a strategy to quantitatively monitor
podocyte turnover from different stem cell niches allowing us to precisely assess and potentially
manipulating the capacity of podocyte regeneration in DN.
Max ERC Funding
1 999 920 €
Duration
Start date: 2014-06-01, End date: 2019-05-31
Project acronym ECAP
Project Genetic/epigenetic basis of ethnic differences in cancer predisposition
Researcher (PI) Gian-Paolo Dotto
Host Institution (HI) UNIVERSITE DE LAUSANNE
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary "Integration of large scale genetic and epigenetic analysis needs to be coupled with well defined biological hypotheses that can be experimentally tested. This project is aimed at developing a novel integrated approach to understand genetic and epigenetic predisposition to cancer with skin as model system.
The Caucasian (West European) and Asian (East Asian) populations differ substantially in their predisposition to skin cancer, specifically Squamous Cell Carcinoma (SCC). The underlying mechanisms are poorly understood. As in other organs, skin SCC results from changes in both epithelial and mesenchymal compartments. We will be focusing on two key gene regulatory networks of cells of the two compartments (keratinocytes and dermal fibroblasts), with a key role in skin SCC. The ""keratinocyte network"" has Notch/p53/p63 as key nodes, while the ""dermal fibroblast network"" had Notch and AP1 family members. We will pursue two main goals :
1) We will test the hypothesis that a linkage can be established between specific genetic and epigenetic marks in the Caucasian versus Asian populations and differences in expression and function of ""keratinocyte and/or dermal fibroblast network genes"".
2) We will test the hypothesis that keratinocytes and/or dermal fibroblasts of Caucasian versus Asian individuals differ in their tumor yielding capability, and that these differences in cancer forming capability are due to differences in either ""keratinocyte or dermal fibroblast network genes"".
The applicant is a world leader in epithelial signaling and cancer biology, and is heading interdisciplinary research efforts that bridge the basic and clinical sciences. Together with his bioinformatician and clinician collaborators, he is in an excellent position to attain the high goals of the proposal. The approach has not been attempted before, is only possible within the frame of an advanced ERC grant, and has substantial basic as well as translational/clinical implications."
Summary
"Integration of large scale genetic and epigenetic analysis needs to be coupled with well defined biological hypotheses that can be experimentally tested. This project is aimed at developing a novel integrated approach to understand genetic and epigenetic predisposition to cancer with skin as model system.
The Caucasian (West European) and Asian (East Asian) populations differ substantially in their predisposition to skin cancer, specifically Squamous Cell Carcinoma (SCC). The underlying mechanisms are poorly understood. As in other organs, skin SCC results from changes in both epithelial and mesenchymal compartments. We will be focusing on two key gene regulatory networks of cells of the two compartments (keratinocytes and dermal fibroblasts), with a key role in skin SCC. The ""keratinocyte network"" has Notch/p53/p63 as key nodes, while the ""dermal fibroblast network"" had Notch and AP1 family members. We will pursue two main goals :
1) We will test the hypothesis that a linkage can be established between specific genetic and epigenetic marks in the Caucasian versus Asian populations and differences in expression and function of ""keratinocyte and/or dermal fibroblast network genes"".
2) We will test the hypothesis that keratinocytes and/or dermal fibroblasts of Caucasian versus Asian individuals differ in their tumor yielding capability, and that these differences in cancer forming capability are due to differences in either ""keratinocyte or dermal fibroblast network genes"".
The applicant is a world leader in epithelial signaling and cancer biology, and is heading interdisciplinary research efforts that bridge the basic and clinical sciences. Together with his bioinformatician and clinician collaborators, he is in an excellent position to attain the high goals of the proposal. The approach has not been attempted before, is only possible within the frame of an advanced ERC grant, and has substantial basic as well as translational/clinical implications."
Max ERC Funding
2 495 425 €
Duration
Start date: 2014-02-01, End date: 2020-01-31
Project acronym editCRC
Project A genome editing-based approach to study the stem cell hierarchy of human colorectal cancers
Researcher (PI) Eduardo Batlle Gómez
Host Institution (HI) FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary A hallmark of cancer is tumor cell heterogeneity, which results from combinations of multiple genetic and epigenetic alterations within an individual tumor. In contrast, we have recently discovered that most human colorectal cancers (CRCs) are composed of mixtures of phenotypically distinct tumor cells organized into a stem cell hierarchy that displays a striking resemblance to the healthy colonic epithelium. We showed that long-term regeneration potential of tumor cells is largely influenced by the position that they occupy within the tumor's hierarchy. To analyze the organization of CRCs without the constraints imposed by tumor cell transplantation experiments, we have developed a method that allows for the first time tracking and manipulating the fate of specific cell populations in whole human tumors. This technology is based on editing the genomes of primary human CRCs cultured in the form of tumor organoids using Zinc-Finger Nucleases to knock-in either lineage tracing or cell ablation alleles in genes that define colorectal cancer stem cells (CRC-SCs) or differentiated-like tumor cells. Edited tumor organoids generate CRCs in mice that reproduce the tumor of origin while carrying the desired genetic modifications. This technological advance opens the gate to perform classical genetic and developmental analysis in human tumors. We will exploit this advantage to address fundamental questions about the cell heterogeneity and organization of human CRCs that cannot be tackled through currently existing experimental approaches such as: Are CRC-SCs the only tumor cell population with long term regenerating potential? Can we cure CRC with anti-CRC-SC specific therapies? Will tumor cell plasticity contribute to the regeneration of the CRC-SC pool after therapy? Do quiescent-SCs regenerate CRC tumors after standard chemotherapy? Can we identify these cells? How do common genetic alterations in CRC influence the CRC hierarchy? Do they affect the stem cell phenotype?
Summary
A hallmark of cancer is tumor cell heterogeneity, which results from combinations of multiple genetic and epigenetic alterations within an individual tumor. In contrast, we have recently discovered that most human colorectal cancers (CRCs) are composed of mixtures of phenotypically distinct tumor cells organized into a stem cell hierarchy that displays a striking resemblance to the healthy colonic epithelium. We showed that long-term regeneration potential of tumor cells is largely influenced by the position that they occupy within the tumor's hierarchy. To analyze the organization of CRCs without the constraints imposed by tumor cell transplantation experiments, we have developed a method that allows for the first time tracking and manipulating the fate of specific cell populations in whole human tumors. This technology is based on editing the genomes of primary human CRCs cultured in the form of tumor organoids using Zinc-Finger Nucleases to knock-in either lineage tracing or cell ablation alleles in genes that define colorectal cancer stem cells (CRC-SCs) or differentiated-like tumor cells. Edited tumor organoids generate CRCs in mice that reproduce the tumor of origin while carrying the desired genetic modifications. This technological advance opens the gate to perform classical genetic and developmental analysis in human tumors. We will exploit this advantage to address fundamental questions about the cell heterogeneity and organization of human CRCs that cannot be tackled through currently existing experimental approaches such as: Are CRC-SCs the only tumor cell population with long term regenerating potential? Can we cure CRC with anti-CRC-SC specific therapies? Will tumor cell plasticity contribute to the regeneration of the CRC-SC pool after therapy? Do quiescent-SCs regenerate CRC tumors after standard chemotherapy? Can we identify these cells? How do common genetic alterations in CRC influence the CRC hierarchy? Do they affect the stem cell phenotype?
Max ERC Funding
2 499 405 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
