Understanding intra-tumor heterogeneity in glioblastoma in space and in time.

Intra-tumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. The mechanistic underpinnings of intra-tumor heterogeneity in progression and therapeutic resistance are however largely unknown. Single-cell RNA-sequencing (scRNA-seq) has revealed significant inter- and intra-tumoral molecular heterogeneity in Glioblastoma (GBM), an aggressive brain tumor that is obstinate to most therapies. However, this technology lacks spatial information resulting from tissue dissociation. This is important as GBMs are also phenotypically heterogeneous and are comprised of specific niches that regulate metabolic needs, immunesurveillance, survival, and invasion, as well as stem cell maintenance. Intra-tumor heterogeneity is therefore likely to be promoted by interactions between tumor cells and their environment. To unravel cell-cell communication in the tissue context, this proposal is aimed at investigating intratumor heterogeneity in a genetically engineered mouse model of GBM using scRNA-seq and spatial transcriptomics, an emerging state-of-the-art technology that allows visualization and quantitative analysis of the transcriptome of single cells with spatial resolution. It provides invaluable information about tumor organisation and the interactions between tumor cells and the local environment. I will zoom into different GBM niches to determine the presence of tumor subclones and how they interact with the tumor vasculature and immune cells.