P08.59 Redefining the cellular architecture of adult and pediatric glioblastomas through large-scale single-cell analyses

While human tumors are shaped by the genetic evolution of cancer cells, evidence also suggests that they display superimposed hierarchies reminiscent of normal development. Yet, relating the genetic and hierarchical models of cancer organization has been limited by technical challenges. Here, studying hemispheric and midline pediatric and adult glioblastomas, we profiled thousands of single cells from fresh tumors by RNA-seq and reconstructed the genetic and epigenetic cellular architecture of tumors in patients. We identified that most cancer cells are differentiated along specialized glial programs, while a subpopulation of cells are undifferentiated and associated with neural stem cell expression programs. By identifying distinct genetic clones, we show that these cellular architectures evolve during the progression of the tumors, suggesting that developmental programs and genetic influences coordinately determine tumor architecture. These results provide unprecedented insight into the cellular composition of brain tumors at single-cell resolution and may help harmonize the cancer stem cell and the genetic models of cancer, with critical implications for disease management