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 MICARUS
Project MicroRNA function in cardiac and metabolic disease
Researcher (PI) Eva Van Rooij
Host Institution (HI) KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary Cardiovascular disease is the primary cause of morbidity and mortality worldwide. Despite numerous treatment options the prevalence of cardiovascular indications continues to increase, underscoring the need for new therapeutic strategies.
In recent years, prominent roles of microRNAs (miRNAs) have been uncovered in a variety of cardiovascular disorders. miRNAs are short, single stranded RNAs that regulate gene expression by suppressing multiple, often related, mRNAs.
Our studies have focussed on the cardiac specific miRNA, miR-208. We showed that, in the setting of heart failure, genetic deletion as well as therapeutic inhibition of miR-208 resulted in reduced cardiac remodeling (less hypertrophy and fibrosis), the inability to upregulate beta-MHC (a sensitive marker of pathological cardiac stress) and improved survival.
Unexpectedly, mice treated with antimiR-208 displayed resistance to obesity and enhanced glucose metabolism in a mouse model of type II diabetes. These effects suggest that the heart plays a previously unrecognized role in systemic metabolic control via a miR-208 dependent mechanism.
Although these studies indicate a crucial role for miR-208 in cardiac remodeling and systemic metabolism, the mechanism of action still remains to be defined. Our preliminary gene expression data indicate a cohort of miR-208 targets to be regulated in our stress models, many of which so far have unknown or ill-studied cardiac functions.
The aim of the present proposal is to use genetics, gene expression analyses, stress models and antimiR approaches to study the relevance of downstream miR-208 targets for cardiac remodeling and total body metabolism and explore whether additional miRNAs besides miR-208 are relevant for cardiometabolic disease. Together these projects will increase our mechanistic understanding of miRNA function in cardiac and metabolic disease which will advance the clinical application of miRNA therapeutics.
Summary
Cardiovascular disease is the primary cause of morbidity and mortality worldwide. Despite numerous treatment options the prevalence of cardiovascular indications continues to increase, underscoring the need for new therapeutic strategies.
In recent years, prominent roles of microRNAs (miRNAs) have been uncovered in a variety of cardiovascular disorders. miRNAs are short, single stranded RNAs that regulate gene expression by suppressing multiple, often related, mRNAs.
Our studies have focussed on the cardiac specific miRNA, miR-208. We showed that, in the setting of heart failure, genetic deletion as well as therapeutic inhibition of miR-208 resulted in reduced cardiac remodeling (less hypertrophy and fibrosis), the inability to upregulate beta-MHC (a sensitive marker of pathological cardiac stress) and improved survival.
Unexpectedly, mice treated with antimiR-208 displayed resistance to obesity and enhanced glucose metabolism in a mouse model of type II diabetes. These effects suggest that the heart plays a previously unrecognized role in systemic metabolic control via a miR-208 dependent mechanism.
Although these studies indicate a crucial role for miR-208 in cardiac remodeling and systemic metabolism, the mechanism of action still remains to be defined. Our preliminary gene expression data indicate a cohort of miR-208 targets to be regulated in our stress models, many of which so far have unknown or ill-studied cardiac functions.
The aim of the present proposal is to use genetics, gene expression analyses, stress models and antimiR approaches to study the relevance of downstream miR-208 targets for cardiac remodeling and total body metabolism and explore whether additional miRNAs besides miR-208 are relevant for cardiometabolic disease. Together these projects will increase our mechanistic understanding of miRNA function in cardiac and metabolic disease which will advance the clinical application of miRNA therapeutics.
Max ERC Funding
2 000 000 €
Duration
Start date: 2014-04-01, End date: 2019-03-31
Project acronym UNICOM
Project The making and breaking of ubiquitin chains in cholesterol metabolism
Researcher (PI) Noam Zelcer
Host Institution (HI) ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM
Call Details Consolidator Grant (CoG), LS4, ERC-2013-CoG
Summary "Elevated levels of circulating LDL-cholesterol are a major determinant contributing to atherogenesis and coronary artery disease. Therefore, many studies address the central transcriptional pathways that regulate cholesterol metabolism. However, transcriptional regulation does not allow cells to quickly adapt to the cholesterol fluxes that they encounter. For this, rapid and reversible post-transcriptional modifications are used, in conjunction with transcriptional control. Ubiquitylation - the post-transcriptional conjugation of ubiquitin to proteins – is studied in relation to many cellular processes. Much less is known about the contribution of the ubiquitin-proteasomal-system (UPS) to regulation of lipid metabolism and development of cardiovascular disease.
I recently identified the E3-ubiquitin ligase IDOL as a novel post-transcriptional regulator of the LDLR pathway. My lab also recently identified two genes, the E3-ubiquitin ligase MARCH6 and the de-ubiquitylase USP2, for which no role in sterol metabolism was known, as important regulators of cellular cholesterol metabolism. With IDOL, these genes control key nodes of cholesterol synthesis and uptake and represent previously unrecognized mechanisms to control cholesterol homeostasis. To study the contribution of these genes to cholesterol metabolism, we will use state-of-the-art mutant mouse models, in vitro assays, and a unique collection of dyslipidemic patient material. Our goal is to characterize the contribution of these genes to cholesterol homeostasis and to examine their involvement in the development of dyslipidemia and atherosclerosis.
Investigating these novel regulatory systems will provide important mechanistic insight into the contribution of the UPS to cholesterol metabolism in health and disease. As components of the UPS are amenable to pharmacological manipulation these studies could potentially lead to novel targets for treatment of hypercholesterolemia and coronary artery disease."
Summary
"Elevated levels of circulating LDL-cholesterol are a major determinant contributing to atherogenesis and coronary artery disease. Therefore, many studies address the central transcriptional pathways that regulate cholesterol metabolism. However, transcriptional regulation does not allow cells to quickly adapt to the cholesterol fluxes that they encounter. For this, rapid and reversible post-transcriptional modifications are used, in conjunction with transcriptional control. Ubiquitylation - the post-transcriptional conjugation of ubiquitin to proteins – is studied in relation to many cellular processes. Much less is known about the contribution of the ubiquitin-proteasomal-system (UPS) to regulation of lipid metabolism and development of cardiovascular disease.
I recently identified the E3-ubiquitin ligase IDOL as a novel post-transcriptional regulator of the LDLR pathway. My lab also recently identified two genes, the E3-ubiquitin ligase MARCH6 and the de-ubiquitylase USP2, for which no role in sterol metabolism was known, as important regulators of cellular cholesterol metabolism. With IDOL, these genes control key nodes of cholesterol synthesis and uptake and represent previously unrecognized mechanisms to control cholesterol homeostasis. To study the contribution of these genes to cholesterol metabolism, we will use state-of-the-art mutant mouse models, in vitro assays, and a unique collection of dyslipidemic patient material. Our goal is to characterize the contribution of these genes to cholesterol homeostasis and to examine their involvement in the development of dyslipidemia and atherosclerosis.
Investigating these novel regulatory systems will provide important mechanistic insight into the contribution of the UPS to cholesterol metabolism in health and disease. As components of the UPS are amenable to pharmacological manipulation these studies could potentially lead to novel targets for treatment of hypercholesterolemia and coronary artery disease."
Max ERC Funding
1 999 998 €
Duration
Start date: 2014-05-01, End date: 2019-04-30
