Molecular cartography of initiating and infiltrating glioma cells using multisector sampling and spatial transcriptomics

About This Grant

SUMMARY Diffuse dissemination of tumor cells into the brain is one of the key problems impacting optimal treatment of gliomas. We hypothesize that distinct types of tumor cells harbor characteristic diffusion patterns. Specifically, we suspect that NPC-like cells predominate in the cortical layers and interact with the laminar extension of neuronal cells in the cortex, while OPC-like cells dominate subcortically and associate with axons and APC-like cells associate with vascular and immune cells. In order to provide four-dimensional reconstructions of tumor development and test our hypotheses, we will perform spatial transcriptomics on n = 254 image-mapped samples from n = 22 distinct tumors (aim 1). Tumor-microenvironment interactions will be evaluated separately for each patient and by comparing distinct locations across patients. Finally, we will develop an agent-based model using n = 179 samples from n = 20 individual with integrated imaging, DNA methylation and DNA sequencing information to reconstruct historical and forecast future tumor development in space and time (aim 2). The findings of these studies will allow for a high-resolution dissection of the identity and location of ancestral stem- like tumor cell populations, as well as the identification of sites of diffuse infiltration. A four-dimensional model of tumor cell dissemination will enable individualized local treatment planning and prognostication.