PhD position: Role of TrkA networks in triple negative breast cancer brain metastasis
Team: Cell Plasticity and Cancer
Mentor: Pr Robert-Alain TOILLON
There are still 12,000 deaths from breast cancer per year in France. The formation of brain metastases is particularly harmful with an average survival of around 4 months for patients with triple negative breast cancer. Canther CNRS 9020-INSERM 1277 (ex INSERM U908) has shown that the Nerve Growth Factor (NGF) and its precursor induce original signaling involving receptor complexes formed by TrkA (NGF receptor), CD44 or EphA2. Only the concomitant inactivation of these complexes decreases the formation of brain metastases in vivo. Based on these original results, we propose to develop a thesis project which aims to characterize the effects of TrkA complexes on brain metastasis in triple negative breast cancers. This project will be carried out in the form of a joint supervision between the Canther lab (Pr Robert-Alain Toillon) and the blood-brain barrier laboratory of Lens (Dr Caroline Mysiorek). In addition, it will be conducted in close collaboration with the HCS pharma company (Dr Nathalie Maubon, director), which is developing specific human organ matrices for organotypic culture in 3-dimensions. All the results obtained within the thesis should allow us 1) to develop models of in vitro studies to study cerebral metastasis 2) to provide a strong understanding of the role of receptor complexes in the appearance and the development of brain metastases. This project should ultimately lead to the realization of translational studies without a priori in metastasis models in order to discover ‘druggable’ targets to develop targeted therapies and thus allow clinical advances.
PhD position: Cellular models, molecular characterization and therapeutic approaches to constitutional epimutations of the MLH1 gene responsible for Lynch syndrome
Team: Mucins, Epithelial Differentiation and Carcinogenesis
Laboratory: CANTHER (Cancer Plasticity, Heterogeneity and Resistance to Therapies), UMR9020 CNRS-1277 Inserm (Dir : Dr Isabelle VAN SEUNINGEN), 59045 Lille cedex
Contact: Julie LECLERC, julie.leclerc(@)inserm.fr / julie.leclerc(@)chru-lille.fr (co-mentor)
Mentor (HDR): Pr Pascal PIGNY
Application deadline: May 4th 2020
PhD beginning: October 1st 2020
Subject: Cellular models, molecular characterization and therapeutic approaches to constitutional epimutations of the MLH1 gene responsible for Lynch syndrome
Abstract: Constitutional epimutations of the MLH1 gene represent an alternative mechanism to genetic mutations in the etiology of Lynch syndrome, which is a cancer predisposition syndrome. Patients with this epigenetic alteration exhibit hypermethylation of MLH1 promoter. Little is known about the molecular mechanisms involved in establishing this hypermethylation. Epimutations were first considered to be nonheritable due to the erasure of epigenetic marks in germ cells, but families with intergenerational transmission of the epimutation, often associated with a cis–acting genetic defect, were then described. We identified distinct genetic events segregating with the hypermethylation in several families (Leclerc et al., Genetics in Medicine 2018).
The aim of the project is to create cellular models of epimutation from pluripotent stem cells, using CRISPR-Cas9 technology to modify the MLH1 gene. These cell models will first enable characterization of the molecular mechanisms involved in the establishment of epigenetic marks and identification of the actors of this targeted hypermethylation. These models will also be used to test demethylating therapies, in order to demonstrate that it is possible to selectively demethylate the promoter of the MLH1 gene.
Skills required: technical skills in cell culture and molecular biology.
PhD position: Collaborative project which aims to discover new pathways/targets with senolityc/senomorphic properties that would limit senescence/aging
Team: Senescence, fibrosis and cancer
Mentor: Dr Olivier PLUQUET
PhD position in senescence and tumorigenesis
A joint PhD position is available in the teams « Senescence, Fibrosis and Cancer » (UMR Canther) located at the Institut Pasteur de Lille (France) and « Stress and Ageing” (URBC-Narilis) located at the University of Namur (Belgium).
We are looking for a dynamic and highly motivated candidate to work on our collaborative project which aims to discover new pathways/targets with senolityc/senomorphic properties that would limit senescence/aging. We are particularly interested in understanding the role of an adaptive signalling pathway called Unfolded Protein Response (UPR) emanating from the endoplasmic reticulum (ER) in this process. The objectives of the project are to comprehensively characterize the functional role played by the UPR in senescence and senescence-associated secretory pathway (SASP), and to determine whether targeting specific branches of the UPR influences the pro-oncogenic SASP properties as well as age-related traits.
The project will use several approaches, including cell imaging, culture of primary cells, and in vivo experiments in mice. The project will involve a close cooperation with other biologists and bioinformaticians/biostatisticians, and will take place in highly competitive scientific infrastructures.
The position will remain open until filled and is available from March 2020 for 42 months.
The candidates of any nationality should have a solid background in molecular and cellular biology (with experience in cell culture and cell signalling) and must hold a master degree in biology, biomedical sciences or equivalent. Practical experience of in vivo biological experimentation would be an asset.
Candidates should send an application letter, a curriculum vitae, a brief summary of research interest, and two reference letters to: Olivier PLUQUET, olivier.pluquet(@)ibl.cnrs.fr and Florence CHAINIAUX, florence.chainiaux(@)unamur.be
PhD position: Computer Simulation and Experiments of Radio-Induced Cell Senescence
Team: Senescence, fibrosis and cancer
Mentor: Pr Corinne ABBADIE