CV Science

Isabelle JANOUEIX-LEROSEY PhD Molecular Biology

Course and current status

Position: Inserm Research Director, class 2.

Professional address:        

Inserm U830 « Genetics and biology of cancers »

Institut Curie, Centre de Recherche, 26 rue d'Ulm

75248 Paris Cedex 05 FRANCE

Tél. : 33 1 56 24 66 84

E-mail : janoueix@curie.fr

Education

• Student at Ecole Normale Supérieure de Saint-Cloud/ Lyon (1986-1990)
• Ph.D. in Molecular Biology from Paris VI University, 1995.
• Habilitation à Diriger les Recherches – Oncology  from Paris V University, 2007

Training and positions

• Ph.D. in the laboratoty directed by Armand Tavitian (Inserm U248), 1989-1992
• Post-doctoral fellow at unit CNRS URA 361 (Institut Pasteur / B. Goud’s team) , 1994-1995
• Inserm recruitment  as researcher, 1995
• Promotion as Research Director, 2010.

Scientific summary

Neuroblastoma is an embryonal cancer of the sympathetic nervous system derived from multipotent neural crest cells (NCCs). It is observed in early childhood and is characterized by a broad spectrum of clinical behaviors, ranging from spontaneous regression to fatal outcome despite aggressive therapies. This cancer accounts for 8-10% of pediatric cancers and 15% of the deaths attributable to malignant conditions in children. The outcome of children with aggressive neuroblastoma remains poor with long-term survival rates still lower than 40%. In order to improve the prognosis of this pediatric cancer and to identify new therapeutic targets, a better understanding of the mechanisms and genes implicated in oncogenesis is required. Interestingly, NB may occur in various contexts, being mostly sporadic but also familial and/or syndromic.

My research program aims at identifying the genes and mechanisms involved in neuroblastoma development and/or progression, with three main axes: (1) study of the heterogeneity and plasticity of cell identity; (2) analysis of the tumor microenvironment and (3) study of the role of MYCN overexpression and Alk mutations in tumorigenesis.

1. Heterogeneity and plasticity of cell identity

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. 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 (MES) and a noradrenergic (NOR) identity and vice versa.

We are now working on a better characterization of the role of cellular reprogramming in tumorigenesis. One of our objectives is to understand the mechanisms that control neuroblastoma cell identity and define the signaling pathways involved in the noradrenergic and mesenchymal cells and in the NOR-MES transition. Our recent results, obtained on cellular models and PDX (Patient Derived Xenograft) models show that external environmental signals and intrinsic factors control plasticity and cell identity in neuroblastoma. Single-cell transcriptomic experiments are ongoing to follow the transition between both identities and get insights into the involved mechanisms and TFs.

2. Deciphering the tumor microenvironment of neuroblastoma

Through collaboration with our colleagues of the SIREDO center, we have recently explored neuroblastoma biopsies from patients by single-cell RNA-seq (10X Genomics technology available at the NGS platform of Institut Curie). Analyses are ongoing to characterize heterogeneity of tumor cells. Furthermore, we also take advantage of these data to decipher the tumor microenvironment of neuroblastoma. In parallel, we investigate mouse tumors generated in the TH-MYCN transgenic model, which constitutes a preclinical model of neuroblastoma in an immunocompetent background. Interactions between different populations of the microenvironment and/or with tumor cells are explored in order to further define therapies targeting, on the one hand, the microenvironment, and, on the other hand, tumor cells.

3. Role of MYCN overexpression and Alk mutations in tumorigenesis

In 2008, the identification of activating mutations of the ALK gene in a subset of sporadic and familial neuroblastomas (Mossé et al, Chen et al, George et al, Janoueix-Lerosey et al, Nature, 2008)) constituted a major advance in the understanding of the disease and opened the way to potential targeted treatments. The ALK gene encodes a tyrosine kinase receptor that is preferentially expressed in the central and peripheral nervous systems. To better understand the early stages of tumorigenesis, we are exploring how overexpression of the MYCN gene (that is amplified in 20% of primary tumors) and/or Alk mutations modify the adrenal gland and the sympathetic ganglia ecosystems. This work is carried out using mouse models, taking advantage of single-cell RNA-seq approaches combined to spatial transcriptomics.