The FRM (Fondation pour la Recherche Médicale, medical research foundation) label has been awarded to six of the Institut Curie Research Center’s teams. These three-year grants help fund research projects for amounts ranging from €200,000 to €400,000 per team (Valérie Borde, Deborah Bourc’his, Emmanuel Farge, Silvia Fre, Franck Perez, Graça Raposo).
Six of the Research Center’s teams have been selected to be awarded the FRM label, for a total of €2.2 million in funding. 53 teams were allocated this funding across France, meaning Institut Curie represents a total of 11% of the country’s beneficiaries.
Recipients’ research projects:
► Valérie Borde: “DNA synthesis control and consequences on fertility and genome stability during double-strand break repair”
► Deborah Bourc’his: “Epigenetic control of fertility by DNA methylation”
► Emmanuel Farge: “Stimulation by mechanotransduction of the Ret/β-cat tumorigenic pathway in heightening the number of stem cells and preclinical therapeutic application in colon cancer in mice”
► Silivia Fre: “Study of the mechanisms involved in controlling differentiation and plasticity in mammals’ stem cells”
► Franck Perez: “Study of the dynamics and mechanisms involved in anterograde and retrograde transport pathways”
► Graça Raposo: “Cellular and molecular bases for pigmentation in humans: physiopathology of intercellular communication towards melanosomes”
Research project summaries:
► Valérie Borde, Chromosome dynamics and recombination team
Project: “DNA synthesis control and consequences on fertility and genome stability during double-strand break repair”
Double-strand breaks in DNA are the most dangerous form of lesions for genomes contained in our cells’ chromosomes. These breaks occur accidentally following exposure to genotoxic agents, or are programmed by cells, such as during the meiosis that produces gametes (ovules and spermatozoids) as part of sexual reproduction. As these breaks are repaired, the stage in which the damaged DNA is rebuilt is risky, as it can engender mutations that are potentially hereditarily harmful. Our project aims to characterize the factors that occur during the new DNA synthesis stage, how these factors are regulated, what the consequences of their deregulation are on fertility, and how cells react to DNA-damaging agents such as those that occur during cancer chemotherapy. For this project, we will be drawing on multiple different experimental systems, from using Saccharomyces cerevisiae yeast to mouse models, and innovative approaches to monitor how DNA is repaired and what the contributing factors are.
► Deborah Bourc’his, Epigenetic decisions and reproduction in mammals team
Project: “Epigenetic control of fertility by DNA methylation”
Reproduction is a fundamental property in all living beings, designed to ensure genetic information is passed down over the generations, thus guaranteeing the continuing existence of species. Reproductive cells, meaning ovules and spermatozoids, have the dual task of acquiring the attributes needed to trigger fertilization, and protecting the DNA they carry from mutations to ensure the ‘right’ information is passed on to the next generation. Any form of interference with one of these functions leads to sterility or developmental abnormalities in the next generation, in turn leading to miscarriages and serious conditions. One of the most dangerous sources of genetic information mutations is transposons, genetic elements that have formed a natural, integral part of our DNA since the beginning of humanity, with the ability to cluster and multiply when not finely controlled. We have millions of copies of transposons in our bodies, with transposable elements making up over half of our DNA, where genes account for just 2% of it. In mammals, a specific epigenetic marker that involves methyl groups attaching to DNA plays a key role in protecting reproductive cells’ identity and integrity against transposons. Our research program focuses on the role played by DNA methylation in reproduction, and more specifically its influence on reproductive cell emergence during development, their specialization in reproducing and protecting the genetic information they carry from transposon activity. This program aims to better understand the root causes of infertility, with most cases unfortunately remaining all too often unexplained, despite an alarming drop in industrialized nations’ fertility rates.
► Emmanuel Farge, Mechanics and genetics of embryo and tumor development team
Project: “Stimulation by mechanotransduction of the Ret/β-cat tumorigenic pathway in heightening the number of stem cells and preclinical therapeutic application in colon cancer in mice”
To date, a certain number of cases of cancer have been found to be caused by mutations of genomes in some cells that lead to uncontrolled growth. The team’s data shows that the mechanical pressures in growing tumors are also likely to trigger deregulations leading to uncontrolled growth in the surrounding healthy tissue. This project aims to test the impact of this mechanical tumor growth in the development of the illness, and to develop new approaches to treatment that inhibit the effects of this mechanical tumorigenic induction in order to make significant progress in fighting the illness. Being awarded the FRM label in 2015 helped us understand which molecules (mechanical molecular sensors) and which colon cells are particularly sensitive to tumor growth pressure and result in tumorigenesis in response to pressure from surrounding tumors. In addition, it allowed us to inhibit the tumorigenesis’ mechanical induction using chemotherapeutic treatment to inhibit these molecular sensors in mice. Finally, it allowed us to demonstrate that the molecular sensors in question are found universally in all animal and human organs, restoring our faith in treatments based on inhibiting tumoral mechanical sensitivity in cancers, which could therefore be universally effective in a wide range of different cancers and organs. The project submitted for renewal of the label in 2019 involves finalizing this work to offer such a therapeutic approach, targeting the mechanically sensitive molecular elements revealed to be the most sensitive and significant in the work carried out for the 2015 label.
► Silivia Fre, Notch signaling in stem cells and tumours team:
Project: “Study of the mechanisms involved in controlling differentiation and plasticity in mammals’ stem cells”
Breast cancer is the most common form of cancer among women in developed countries. One of the mechanisms by which cancer develops involves the programs that maintain stem cells being deregulated. As a result, understanding the mechanisms by which normal stem cells develop will be crucial to understanding how and why these programs can be deregulated and lead to cancer. Mammals’ pluripotent stem cells are cells that can differentiate into different types of cells and are responsible for embryonic development in mammals. However, over the course of adulthood, unipotent progenitors that can only differentiate into a single type of cell replace the pluripotent stem cells. Although little is known on how stem cells in mammals evolve from pluripotent to unipotent, our laboratory recently discovered that mammals’ stem cells become unipotent very early on in mammogenesis. The aim of the project presented here is to determine how normal embryonic (pluripotent) and adult (unipotent) stem cells develop in mammals, in order to pinpoint the moment at which the stem cells become cells or go on to another specific differentiation. Cutting-edge technology will be used to explore the mechanisms that regulate how the cells shift from pluripotent to unipotent. Understanding these mechanisms will help us understand how normal unipotent cells can be restored to a pluripotent state similar to embryonic stem cells – the mechanism that leads to cancer. These findings will help in identifying early-stage breast cancer, as well as in discovering new treatment targets.
► Franck Perez,Dynamics of intracellular organization team
Project: “Study of the dynamics and mechanisms involved in anterograde and retrograde transport pathways”
To ensure their survival and specific functions, eukaryotic cells must continuously transport proteins to specific compartments: plasma membrane or internal compartments. The Golgi apparatus is the central organelle that modifies and sorts proteins in the secretory pathways (anterograde pathway) and proteins in retrograde transport. Defects in these pathways are linked to various pathologies, from developmental disorders or neuronal degeneration to some types of cancer. How the Golgi apparatus is able to control these two-way pathways and what the ensuing impact of these routes is on how the Golgi apparatus is structured, remains little-known. We have developed a system called RUSH, which allows us to analyze and quantify anterograde transport in a huge range of proteins. In this project, we will be developing a quantitative study system into retrograde transport pathways (retroRUSH). Using these two systems will enable us to analyze the sorting process and the effect membrane pathways have on the Golgi apparatus as well as interferences between the anterograde and retrograde pathways. In the project’s second phase, we will be studying the role proteins linked to the Golgi apparatus play in controlling these pathways. Some of these factors are directly responsible for the development of human pathologies. However, many studies suggest that long-term inactivation of these factors allow the cells to adapt and mask the fundamental effects of these deficiencies. Furthermore, some of these factors have essential functions that prevent the impact of their inactivation from being directly studied. For all these reasons, we will be implementing methods that allow these factors to be acutely inactivated, thus allowing us to study the roles they play in real time.
► Graça Raposo, Structure and membrane compartments team
Project: “Cellular and molecular bases for pigmentation in humans: physiopathology of intercellular communication towards melanosomes”
In skin melanocytes, melanin pigment is synthesized in structures called melanosomes, which are transferred to neighboring keratinocytes to be colored and protect skin from UV rays. Our project pinpoints the mechanisms involved in communication between melanocytes and keratinocytes, both of which are affected in genetic pigmentary disorders and types of skin cancer such as melanoma. We will characterize the messengers or extra-cellular vesicles involved in communication between melanocytes and keratinocytes as well as their role(s) in skin homeostasis. We will study how pigment in keratinocytes evolves depending on skin type, in particular how it is formed and maintained in melanosome reservoirs via the role played by extra-cellular vesicles and their content. We will study the mechanisms underpinning the differences in how melanosomes are distributed in skin types with high and low pigmentation. Through this project, we will be identifying new mechanisms necessary to normal skin pigmentation, as well as pathological processes that will pave the way for new avenues of treatment.