Charting the cellular, genetic and environmental landscapes of Gliomas at single-cell resolution

Gliomas are a notoriously diverse family of cancers whose heterogeneity is manifested at several layers of resolution. At the finest level, Glioma heterogeneity can be understood as a function of transcriptionally-distinct subpopulations of cancer cells or cellular ‘states’ whose emergence results from the interplay of genetic, environmental and lineage-derived cues. These cellular states are increasingly appreciated to preferentially govern critical aspects of Glioma biology such as tumour growth and resistance to treatment. Moreover, their drivers can promote or deplete certain states by modulation of cellular dynamics: state-specific rates of cell growth, cell death and cellular transitions. These observations have far-reaching implications for basic cancer research as well as for therapeutics yet the cellular landscapes of many Glioma types remain uncharted and their associated drivers unknown. We perform comprehensive scRNA-seq studies to characterise the cancer cellular states and associated drivers across major types of Glioma. In IDH-wildtype Glioblastoma, the ­­­most common and aggressive of all brain cancers, we further delineate the cellular trajectories between states, bringing us closer to novel drug therapies that will successfully eliminate all cancer states, push them to terminal differentiation and/or abolish their trajectories. Finally, we conduct pan-Glioma analyses to map the contributions of specific genetic, microenvironmental and lineage-derived profiles to distinctions between types. By delineating the similarities and differences between Glioma types, we provide a more general framework to help us understand these fatal malignancies.