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Epithelial sheets are crucial components of all metazoan animals, enclosing organs and protecting the animal from its environment.  Epithelial homeostasis poses unique challenges, as addition of new cells and loss of old cells must be achieved without disrupting the fluid-tight barrier and apicobasal polarity of the epithelial sheet.  Several studies have identified genetic and cell biological mechanisms underlying extrusion and delamination of cells from epithelia, but far less is known of the converse mechanism by which new cells are added.  Here, we combine molecular, pharmacological and laser-dissection experiments with quantitative physical modeling to characterize forces driving emergence of a new apical surface as nascent cells are added to a vertebrate epithelium in vivo.  We find that this process involves an interplay between cell-autonomous actin-generated forces in the emerging cell and the mechanical properties of neighboring cells.  Our findings define the forces driving a novel cell behavior, and by complementing previous studies of delamination and extrusion, they provide a more comprehensive understanding of epithelial homeostasis.

The obligate intracellular parasite Toxoplasma gondii strikes a subtle balance with the host immune system that not only prevents host death but also promotes parasite persistence. Although being enclosed within a parasitophorous vacuole (PV), the parasite actively interfaces with host cell signaling pathways, thereby directing host cell responses. The PV membrane has been regarded as a sieve limiting the delivery of proteins secreted by the parasite beyond the vacuolar space. However, the discovery of a large variety of effector proteins originating from dense granule organelles (GRA proteins) and their remarkable ability to cross the PV membrane and to accumulate in the host cell nucleus has changed this paradigm. With this new repertoire of molecular weapons, it can target gene expression at both the transcriptional and posttranscriptional levels by regulating the amount of mRNAs encoding proteins and affecting noncoding RNAs, e.g., microRNAs, respectively. These effectors highlight novel mechanisms by which T. gondii has learned to harness host signaling to favor intracellular survival and will guide future studies designed to uncover the additional complexity of this intricate host-pathogen interaction.

Our genetic material (DNA) is continually subjected to damage, either from endogenous sources such as reactive oxygen species that arise as by-products of oxidative metabolism, from the breakdown of replication forks during cell growth, or by agents in the environment such as ionizing radiation or carcinogenic chemicals. To cope with such damage, cells employ a variety of repair processes that are specialized to recognize different types of lesions in DNA. These repair systems are essential for the maintenance of genome integrity and for cancer avoidance.

The focus of our research is to determine the mechanisms for repair and to define the cellular defects that lead to cancers and neurodegeneration, two common consequences of defective damage processing. In particular our efforts focus on the mechanisms of homologous recombination, which are important for the repair of double-strand breaks in DNA. Defects in this process lead to cancer predisposition, in particular breast cancers caused by mutation of the BRCA2 gene, acute leukemias associated with Fanconi anemia, and a wide range of cancers found in individuals with the chromosome instability disorder known as Bloom's syndrome. Over the years, many of the proteins required for recombinational repair have been purified in our laboratory, and we use biochemical, structural, and molecular and cell biological approaches to understand how they bring about the repair of DNA breaks. Of particular interest are the roles of the BRCA2 tumour suppressor and the RAD51 recombinase in mediating the initiation of recombinational repair. Studies of the enzymes (MUS81-EME1 and GEN1) that mediate the resolution of DNA recombination intermediates (e.g. Holliday junctions) reveals an unexpectedly tightly controlled system that is essential not just for the completion of recombinational repair, but also for the proper segregation of DNA at mitosis. The lecture will describe our current understanding of recombinational repair and why defects in this process leads to human disease.

It has been well established that pathogenic germline mutations in genes like TP53, PTCH1, SUFU, APC, NF1, SMARCB1, SMARCA4, BRCA2 and the MMR genes are associated with an increased incidence of brain tumors. Most of them are associated with a specific type of brain tumor. It has been estimated that as many as 7-10% of all pediatric tumors (and brain tumors) are based on a highly penetrant germline mutation. However, this might still be an under-appreciation of this enormous clinical and scientific challenge. We have recently shown that ~20% of SHH-driven medulloblastomas have an underlying germline mutation in TP53, PTCH1, SUFU, BRCA2 or PALB2 when only focusing on known cancer predisposition genes. When then doing an unbiased genome-wide screen investigating all genes for truncating germline variants that are exceedingly rare in the normal population, we were able to identify another highly prevalent medulloblastoma predisposition gene, which we are currently futher analyzing in terms of co-occuring mutations and functional impact. This new finding increases the rate of SHH medulloblastomas with a clear germline predisposition to ~30%. It is very likely that similar findings will also further increase this proportion in other pediatric cancers. We are trying to address this question by a genome-wide pediatric cancer germline analysis performed on all publicly available data.

It is a pleasure to invite you to this meeting, which is organised by the RADIATE-ITN and will take place at the Institut Curie Paris, France on 12 October 2018. RADIATE is an innovative training network funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No: 642623.

This meeting is part of Outreach activities by the RADIATE-ITN and is aimed particularly at young researchers. With talks by leading international investigators and poster sessions dedicated to research in the field of radiation biology and oncology, this promises to be a highly interactive and informative meeting.

The theme of IMSCM2018 will be the use of radiation biology in the treatment of cancer.

Topics of interest: Tumour Microenvironment; DNA Repair; Immune Response; Innovative Therapies.

Keynote Speakers: Thomas Helleday, Karolinska Institutet; Rob Coppes, Groningen University Medical Center; Andy Minn, University of Pennsylvania; Mark Dewhirst, Duke University; Mark de Ridder, Vrije Universiteit Brussel; Marie Dutreix, Institut Curie; Ester Hammond, University of Oxford; Sylvia Formenti, Weill Cornell Medical College.

Further details of the Programme, including the Keynote speakers can be found on our conference website.

Important Dates:

Deadline for early bird registration: 30 April 2018

Deadline for abstract submission: 13 August 2018 

Deadline for registration: 15 September 2018

Abstract submission can be found on our website.

All abstracts must be sent to radiate@oncology.ox.ac.uk. For any enquiries regarding the programme, and all general enquiries, please contact: radiate@oncology.ox.ac.uk

We look forward to seeing you at IMSCM2018 in Paris!

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Séminaire proposé par Marie Dutreix

Tiago Faial obtained his Ph.D. from the Stem Cell and Developmental Biology program at the University of Cambridge under the supervision of Jim Smith and Roger Pedersen, where he studied gene regulatory networks and signaling cascades that underpin mesoderm differentiation. For his postdoctoral work, Tiago joined Joanna Wysocka's laboratory at Stanford University where he studied the dynamics of epigenetic landscapes in pluripotency. He joined the Nature Genetics editorial team in 2015.​

Title & abstract to come.

Title & abstract to come.