Francois Guillemot & Simona Parrinello

 

Regulation of stem cell quiescence in normal neurogenesis and brain cancer

NOTE:

Non-EU applicants are not eligible for the funding for this project.

In the adult mammalian brain neural stem cells (NSCs) persist in restricted germinal regions where they continuously generate new neurons and glia. The majority of NSCs are actively maintained in a quiescent or slow-dividing state, to prevent depletion and sustain life-long neurogenesis. Quiescence is controlled by a complex interplay between intrinsic programs and extrinsic cues from the microenvironment, or niche, in which the stem cells reside.

Glioblastoma, (GBM), the most common and aggressive type of brain cancer, are driven by tumour-propagating cells with neural stem cells properties, termed glioma stem-like cells (GSCs). Similar to their normal NSC counterparts, GSCs reside in specialised niches that control their behaviour and are relatively quiescent. Quiescence is thought to protect GSC from chemo-therapeutic agents that target proliferative cells and thus greatly contribute to GBM therapeutic resistance and recurrence. Furthermore, GSC quiescence is not as tightly controlled as NSC quiescence, leading to deregulated self-renewal and aberrant tumour growth. Understanding GSC quiescence and how it differs from NSC quiescence is therefore important for identifying novel therapeutic strategies for this devastating disease.

As part of the CRUK Brain tumour Accelerator programme, this project will focus on identifying the molecular mechanisms that underlie GSC quiescence. To achieve this, we will take advantage of in vitro models of NSC quiescence previously developed in the laboratory and combine them with genetically-defined mouse GSC models that mimic human GBM. Transcriptomic (RNA-Seq) and epigenomic profiling approaches (ChIP-Seq, ATAC-Seq) will be carried out on actively proliferating and quiescent NSCs and GSCs to identify gene regulatory networks and signalling pathways that underlie GSC quiescence. By comparing NSC and GSC, we will also determine how normal quiescence controls become deregulated in GBM. Key mediators will then be assessed in vivo in gain and loss-of-function experiments to determine effects on tumour growth and response to chemotherapy. These studies will provide important insights in the biology of GBM and the mechanisms whereby GSCs drive tumour malignancy and recurrence.