Cellular plasticity and epigenetic remodeling

Type de poste
Niveau d'étude minimal
Dates
Durée du poste
Contrat renouvelable
Contrat non renouvelable
Date de prise de fonction
Date de fin de validité de l'annonce
Localisation
Nom de la structure d'accueil
Adresse

26 rue d'Ulm
75005 Paris
France

Contacts
Isabelle Janoueix
Valentina Boeva
Email du/des contacts
janoueix@curie.fr
Valentina.Boeva@inserm.fr
Description

Context

The laboratory “Genetics and Biology of Pediatric Tumors” directed by Olivier Delattre at the Curie Institute develops several research programs to understand the biology and oncogenic transformation mechanisms of various pediatric tumors. We are particularly interested in the mechanisms that govern cellular plasticity in childhood cancers and their role in treatment resistance. The Curie Institute provides an excellent scientific environment for high quality research with state-of-the-art equipment as well as a constellation of seminars covering many research areas.
The successful applicant joining the neuroblastoma team will work on a research project funded by INCa and led by Isabelle Janoueix-Lerosey, in collaboration with the laboratory of Valentina Boeva (ETH Zürich), a world-class expert in computational epigenetics in cancer.

Research project

Tumor cell plasticity has now been identified as a source of intra-tumor heterogeneity that may contribute to treatment failure in several types of cancer. To further explore the mechanisms of plasticity and their link with epigenetic remodeling, we will focus on neuroblastoma, a tumor of the sympathetic nervous system, derived from multipotent neural crest cells (NCC), which accounts for around 15% of children cancer-related deaths. High-Risk neuroblastoma most often initially responds to intensive chemotherapy; however, relapses frequently occur followed by fatal outcome. Through the analysis of the super-enhancer landscape, we recently revealed two types of cell identity in neuroblastoma: a sympathetic noradrenergic identity and a NCC-like identity, driven by a module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs) and a module containing AP-1 TF, respectively (Boeva et al, Nature Genetics, 2017). We showed that NCC-like cells display mesenchymal features and are less sensitive to chemotherapy. Recent evidence indicates that some neuroblastoma cells exhibit plasticity and are able to shift between an NCC-like/mesenchymal and a noradrenergic identity and vice versa.
This offer provides an opportunity to work on a multifaceted biological problem by developing and applying methods for integrative high-throughput data analysis. Your aim would be to investigate neuroblastoma cell identity, plasticity and heterogeneity using bioinformatics and computational biology approaches, in particular through the analysis of cancer cell ChIP-seq and RNA-seq data, both at the bulk and single cell level. The whole project will contribute to a better characterization of the role of cellular reprogramming in tumorigenesis and will eventually help choice of treatment of neuroblastoma patients.

Requirements
We are looking for a candidate highly motivated to work with big data, particularly with single cell transcriptomic data and dig into cancer epigenetics. A master’s degree, experience in bioinformatics analysis (in R), and proficiency in English are required. Programming skills (Perl/Python), computational and mathematical background and/or experience in cellular and molecular biology would be a plus.

How to apply

The position (2 years) is available starting September 1, 2019 or latter. Please apply by sending your CV and publication list together with a motivation letter and the names of two references to:
janoueix@curie.fr and Valentina.Boeva@inserm.fr. Please indicate “Engineer position application U830” in the subject of your email.

Selected publications of the team

Lopez-Delisle L, Pierre-Eugène C, Louis-Brennetot C, Surdez D, Raynal V, Baulande S, Boeva V, Grossetête-Lalami S, Combaret V, Peuchmaur M, Delattre O and Janoueix-Lerosey I. Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis. Oncogene (2018) 37:1417-1429.

Boeva V, Louis-Brennetot C, Peltier A, Durand S, Pierre-Eugène C, Raynal V, Etchevers HC, Thomas S, Lermine A, Daudigeos-Dubus E, Geoerger B, Orth MF, Grünewald TGP, Diaz E, Ducos B, Surdez D, Carcaboso AM, Medvedeva I, Deller T, Combaret V, Lapouble E, Pierron G, Grossetête-Lalami S, Baulande S, Schleiermacher G, Barillot E, Rohrer H, Delattre O, Janoueix-Lerosey I. Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries. Nat Genet. (2017) 49:1408-1413.

Hashoor H, Louis-Brennetot C, Janoueix-Lerosey I, Bajic VB, and Boeva V. HMCan-diff: a method to detect changes in histone modifications in cells with different genetic characteristics. Nucleic Acids Research. (2017) 45(8):e58.

Deveau P, … Janoueix-Lerosey I, Barillot E, Delattre O, Maris J, Schleiermacher G, and Boeva V. QuantumClone: Clonal assessment of functional mutations in cancer based on a genotype-aware method for clonal reconstruction. Bioinformatics (2018) 34(11):1808-1816.

Cazes A, Lopez-Delisle L, Tsarovina K, Pierre-Eugène C, De Preter K, Peuchmaur M, Nicolas A, Provost C, Louis-Brennetot C, Daveau R, Kumps C, Cascone I, Schleiermacher G, Prignon A, Speleman F, Rohrer H, Delattre O, Janoueix-Lerosey I. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma. Oncotarget (2014) 5: 2688-2702.

Cazes A, Louis-Brennetot C, Mazot P, Dingli F, Lombard B, Boeva V, Daveau R, Cappo J, Combaret V, Schleiermacher G, Jouannet S, Ferrand S, Pierron G, Barillot E, Loew D, Vigny M, Delattre O, Janoueix-Lerosey I. Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma. Cancer Res. (2013) 73:195-204.

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