Project acronym InMec
Project Inside mechanisms sustaining cancer stem cells
Researcher (PI) Pier Giuseppe Pelicci
Host Institution (HI) ISTITUTO EUROPEO DI ONCOLOGIA SRL
Call Details Advanced Grant (AdG), LS4, ERC-2013-ADG
Summary The “Cancer Stem Cell (CSC) Hypothesis” postulates that the capacity to maintain tumour growth is owned by rare cancer cells, the CSCs, endowed with self-renewal properties. This hypothesis implies that CSCs must be eliminated to achieve cancer cure. Nevertheless, direct proof is still lacking, and recent findings challenge our concepts of CSCs, showing the limits of the CSC-defining assay (transplantation) and suggesting that CSC-identity might be context-dependent. We found two properties of CSCs self-renewal that are indispensable for the maintenance of an expanding CSC-pool and tumour growth: increased frequency of symmetric divisions, due to inactivation of the p53 tumour suppressor, and increased replicative potential, due to up-regulation of the cell-cycle inhibitor p21. We will now investigate: i) How loss of p53 in tumours leads to expansion of the CSC pool, by testing the hypothesis that p53-loss activates the Myc oncogene which induces CSC-reprogramming of differentiated cancer cells. ii) Whether p53-independent pathways are also implicated, by in vivo shRNA screens of primary tumours or normal progenitors to identify pathways involved, respectively, in CSC self-renewal or inhibition of SC-reprogramming. iii) How p21-induced cell-cycle arrest protects CSCs from self-renewal exhaustion, by investigating regulation of cell-cycle recruitment of quiescent CSCs. iv) Whether activation of p21 in CSCs induces a mutator phenotype, due to its ability to activate DNA repair, by investigating mechanisms of DNA-damage, mutation rates, and relevance of CSC mutations for development of chemoresistance. We will test self-renewal functions in a transplantation-independent assay, based on tumour re-growth in vivo after cytotoxic treatments and “clonal tracking” of re-growing tumours (using barcoded lentiviral libraries). Our long-term goal is the identification of CSC-specific targets that could be used to create the basis for CSC-specific pharmacological intervention.
Summary
The “Cancer Stem Cell (CSC) Hypothesis” postulates that the capacity to maintain tumour growth is owned by rare cancer cells, the CSCs, endowed with self-renewal properties. This hypothesis implies that CSCs must be eliminated to achieve cancer cure. Nevertheless, direct proof is still lacking, and recent findings challenge our concepts of CSCs, showing the limits of the CSC-defining assay (transplantation) and suggesting that CSC-identity might be context-dependent. We found two properties of CSCs self-renewal that are indispensable for the maintenance of an expanding CSC-pool and tumour growth: increased frequency of symmetric divisions, due to inactivation of the p53 tumour suppressor, and increased replicative potential, due to up-regulation of the cell-cycle inhibitor p21. We will now investigate: i) How loss of p53 in tumours leads to expansion of the CSC pool, by testing the hypothesis that p53-loss activates the Myc oncogene which induces CSC-reprogramming of differentiated cancer cells. ii) Whether p53-independent pathways are also implicated, by in vivo shRNA screens of primary tumours or normal progenitors to identify pathways involved, respectively, in CSC self-renewal or inhibition of SC-reprogramming. iii) How p21-induced cell-cycle arrest protects CSCs from self-renewal exhaustion, by investigating regulation of cell-cycle recruitment of quiescent CSCs. iv) Whether activation of p21 in CSCs induces a mutator phenotype, due to its ability to activate DNA repair, by investigating mechanisms of DNA-damage, mutation rates, and relevance of CSC mutations for development of chemoresistance. We will test self-renewal functions in a transplantation-independent assay, based on tumour re-growth in vivo after cytotoxic treatments and “clonal tracking” of re-growing tumours (using barcoded lentiviral libraries). Our long-term goal is the identification of CSC-specific targets that could be used to create the basis for CSC-specific pharmacological intervention.
Max ERC Funding
2 500 000 €
Duration
Start date: 2014-07-01, End date: 2019-06-30
Project acronym METARNAFLAMMATION
Project The RNA bridge between IRE-1 and PKR leading to metaflammation: discovery and intervention in atherosclerosis
Researcher (PI) Ebru Erbay
Host Institution (HI) BILKENT UNIVERSITESI VAKIF
Call Details Starting Grant (StG), LS4, ERC-2013-StG
Summary A close functional and molecular integration between metabolic and immune systems is crucial for systemic homeostasis and its’ deregulation is causally linked to obesity and associated diseases including insulin resistance, diabetes and atherosclerosis and known as cardiometabolic syndrome (CMS). Metabolic overload initiates a chronic inflammatory and stress response known as metaflammation and promotes the complications of CMS. The precise molecular mechanisms linking metabolic stress to immune activation and stress responses, however, remain elusive.
Earlier studies demonstrated metabolic overload stresses the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR). ER is a critical intracellular metabolic hub orchestrating protein, lipid and calcium metabolism. These vital functions of ER are maintained by a conserved, adaptive stress response or UPR that emanates from its membranes. ER stress has emerged as a central paradigm in the pathogenesis of CMS and its reduction prevents atherosclerosis and promotes insulin sensitivity. However, a clear understanding of how metabolic stress is sensed and communicated by the ER is fundamental in designing specific and targeted therapy to ER stress in CMS. This application will investigate the ER stress response that can sense excess lipids and couple to inflammatory and stress responses, and whether its unique operation under metabolic stress can be suitable for therapeutic exploitation in CMS. This proposal tackles the unique modes of operation of two important players in the ER stress response that are coupled by metabolic stress, inositol-requiring enzyme-1 (IRE-1) and double-stranded RNA-activated kinase (PKR), by taking advantage of chemical-genetics to specifically modify their activities. When completed the proposed studies will have shed light on a little explored but central question in the field of immunometabolism regarding how nutrients engage inflammatory and stress pathways.
Summary
A close functional and molecular integration between metabolic and immune systems is crucial for systemic homeostasis and its’ deregulation is causally linked to obesity and associated diseases including insulin resistance, diabetes and atherosclerosis and known as cardiometabolic syndrome (CMS). Metabolic overload initiates a chronic inflammatory and stress response known as metaflammation and promotes the complications of CMS. The precise molecular mechanisms linking metabolic stress to immune activation and stress responses, however, remain elusive.
Earlier studies demonstrated metabolic overload stresses the endoplasmic reticulum (ER) and activates the unfolded protein response (UPR). ER is a critical intracellular metabolic hub orchestrating protein, lipid and calcium metabolism. These vital functions of ER are maintained by a conserved, adaptive stress response or UPR that emanates from its membranes. ER stress has emerged as a central paradigm in the pathogenesis of CMS and its reduction prevents atherosclerosis and promotes insulin sensitivity. However, a clear understanding of how metabolic stress is sensed and communicated by the ER is fundamental in designing specific and targeted therapy to ER stress in CMS. This application will investigate the ER stress response that can sense excess lipids and couple to inflammatory and stress responses, and whether its unique operation under metabolic stress can be suitable for therapeutic exploitation in CMS. This proposal tackles the unique modes of operation of two important players in the ER stress response that are coupled by metabolic stress, inositol-requiring enzyme-1 (IRE-1) and double-stranded RNA-activated kinase (PKR), by taking advantage of chemical-genetics to specifically modify their activities. When completed the proposed studies will have shed light on a little explored but central question in the field of immunometabolism regarding how nutrients engage inflammatory and stress pathways.
Max ERC Funding
1 362 921 €
Duration
Start date: 2014-01-01, End date: 2018-06-30
Project acronym WEAR3D
Project Wearable Augmented Reality 3D Displays
Researcher (PI) Hakan Urey
Host Institution (HI) KOC UNIVERSITY
Call Details Advanced Grant (AdG), PE7, ERC-2013-ADG
Summary Wearable displays have advanced rapidly over the past few decades but they are limited in field-of-view due to optical constraints. Likewise, 3D displays have several technological and viewing discomfort limitations. These limitations result from the missing 3D depth cues in stereoscopic displays, which are essential for real 3D and for interactive augmented reality (AR) applications. Wear3D proposal aims to overcome the two fundamental scientific challenges of wearable displays and make them as natural as wearing a pair of eyeglasses: (i) Eliminate the relay lenses. We need to overcome the focusing problem of the eyes in order to completely eliminate the large relay lenses. As a result, miniaturization of wearable displays will be possible by taking full advantage of the advancements in micro-technologies; (ii) Provide all the essential 3D depth cues to avoid perceptual errors and viewing discomfort. We need to enable the two eyes to fixate at the correct depth of the objects rather than the display panel without losing resolution. Thereby, eliminating the conflict between the accommodation and convergence. Overcoming these challenges would enable a display which can provide natural looking and interactive 3D and very wide field-of-view (>100deg) in an eyeglasses form factor. Such a display goes far beyond the state-of-the art in wearable displays and open new research directions for intelligent human-computer interfaces and AR.
Summary
Wearable displays have advanced rapidly over the past few decades but they are limited in field-of-view due to optical constraints. Likewise, 3D displays have several technological and viewing discomfort limitations. These limitations result from the missing 3D depth cues in stereoscopic displays, which are essential for real 3D and for interactive augmented reality (AR) applications. Wear3D proposal aims to overcome the two fundamental scientific challenges of wearable displays and make them as natural as wearing a pair of eyeglasses: (i) Eliminate the relay lenses. We need to overcome the focusing problem of the eyes in order to completely eliminate the large relay lenses. As a result, miniaturization of wearable displays will be possible by taking full advantage of the advancements in micro-technologies; (ii) Provide all the essential 3D depth cues to avoid perceptual errors and viewing discomfort. We need to enable the two eyes to fixate at the correct depth of the objects rather than the display panel without losing resolution. Thereby, eliminating the conflict between the accommodation and convergence. Overcoming these challenges would enable a display which can provide natural looking and interactive 3D and very wide field-of-view (>100deg) in an eyeglasses form factor. Such a display goes far beyond the state-of-the art in wearable displays and open new research directions for intelligent human-computer interfaces and AR.
Max ERC Funding
2 496 525 €
Duration
Start date: 2014-01-01, End date: 2018-12-31
