Understanding intra-tumor heterogeneity and its implication in therapeutic resistance with spatial transcriptomics in space and time

Intra-tumor heterogeneity is the main obstacle to effective cancer treatment and personalized medicine. It provides adaptations to response and selection for treatment-resistant subclones. The mechanistic underpinnings of intra-tumor heterogeneity in progression and therapeutic resistance are however largely unknown. Single-cell RNA-sequencing 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 vascular niches that regulate metabolic needs, immune-surveillance, survival, and invasion, as well as stem cell maintenance. Intra-tumoral heterogeneity is therefore likely to be promoted by interactions between tumor cell clones and their environment, with immune and other stromal factors influencing malignant progression and therapeutic resistance. To unravel cell-cell communication in the tissue context, this proposal is aimed at investigating intra-tumor heterogeneity in a genetically engineered mouse model of GBM using 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 spatial information about tumor organization and the interactions between tumor cells and the local environment. I will zoom into the area of vascular niches to determine the presence of tumor subclones and how they interact with the tumor vasculature and neighbor immune cells by expression profiling of single cells. I will then investigate how the different niche cell types and tumor subclones respond, and adapt to treatments that alter the vascular niche using an antiangiogenic immune-modulating therapy, currently used in clinical trials for GBM.