Mots-Clés

Bioinformatics Genomics Cancer Biology Pediatric Oncology Alternative splicing

Description

Master 1 or Master 2 internship: Please reach me out by email: olivier.saulnier@curie.fr

Background

Medulloblastoma (MB) is a highly malignant embryonal brain tumor predominantly affecting children and adolescents. Over the years, genomics have transformed our understanding of this complex disease, leading to its subclassification into distinct molecular subgroups. This classification is not only crucial for prognostic and therapeutic purposes but also sheds light on the developmental origins of this deadly cancer. Medulloblastoma can be broadly categorized into four molecular subgroups: WNT, Sonic Hedgehog (SHH), Group 3, and Group 4. These subgroups exhibit profound differences in their genetic alterations, gene expression profiles, clinical characteristics, and, most notably, their cell of origin. Each subgroup is thought to originate from distinct cells within the cerebellum and understanding these distinct diseases is crucial for tailoring precise treatment strategies. The WNT subgroup is believed to emanate from the lower rhombic-lip (RL) in the developing cerebellum, a critical region for early cerebellar development. In contrast, the SHH subgroup is associated with cells derived from the external granule layer (EGL), a transient structure in the developing cerebellum responsible for the production of granule neuron precursors. The Group 3 and Group 4 MB subgroups appear to arise from the rhombic-lip (RL), which produces 80% of all the neurons in our entire brain. Recently it has been shown that the RL splits into two zones: a ventral stem cell zone (RLVZ) and a dorsal progenitor cell zone (RLSVZ) and that this split is specific to humans (and not observed in the RL of mice or macaques). We, and others, have identified that Group 3 MB have its roots in stem cell residing within the rhombic-lip ventricular zone (RLVZ), while Group 4 MB is composed of undifferentiated cells from the rhombic lip subventricular zone (RLSVZ). These distinct cellular origins provide important insights into the developmental processes that are dysregulated and providing potential therapeutic targets. However, these studies do not consider the role of post-transcriptional mechanisms, such as alternative splicing of mRNAs, as a determinant of cell fate decisions and MB oncogenesis.

Objectives

We hypothesize that the identification of splicing defects in Medulloblastoma will lead to uncover post-transcriptional processes altered in MB and will provide key insight into essential biological differences between the normal human hindbrain development and oncogenesis of this deadly cancer. 

The goal of this internship is to develop a new tool to allow a custom gene set enrichment analysis using alternative splicing results. The aim is to scrap pubmed (or published databases, GEO, SRA, BioRxiv), to extract splicing matrixes and to perform comparison with a dataset of interest. Ultimately, we will be able to propose biological pathways that are involved at the post-transcriptional level.

Please reach me out by email: olivier.saulnier@curie.fr