STEM-22LARGE-SCALE SINGLE-CELL RNA-seq REVEALS A DEVELOPMENTAL CELLULAR HIERARCHY IN HUMAN OLIGODENDROGLIOMA

The heterogeneity among tumor cells within human glioma underlie their ability resist chemotherapy and radiation, ultimately leading to disease progression. While current chemotherapy and radiation treatment focuses on the effect on bulk tumor, mounting evidence indicates that rarer subpopulations of tumor cells are endowed with stem-like properties, which are capable of resisting these treatments, proliferating, and causing more aggressive recurrent tumors. However, unbiased evidence for cancer stem-like cells (CSCs) in solid human malignancies remains elusive. To better understand intratumoral heterogeneity, we sequenced the transcriptome of 3,348 single cells from human oligodendrogliomas using RNA-seq and reconstructed the cellular architecture within freshly resected tumor specimens from consented patients. We found that most tumor cells are differentiated along two specialized glial programs, while a third, rarer subpopulation of tumor cells express a neural stem/progenitor-like program. Surprisingly, cellular proliferation was restricted to this rare stem/progenitor-like subpopulation, consistent with the existence of a stem/progenitor-like compartment that is solely responsible for fueling growth of oligodendrogliomas in humans. By studying chromosomal copy number variation, we detect distinct genetic clones in which these three tumor subpopulations are preserved, indicating that the cellular hierarchy and genetic influences together determine tumor architecture. These results provide unprecedented insight into the cellular composition of brain tumors at single-cell resolution and have the potential to harmonize the cancer stem cell and genetic models of cancer, with critical implications for disease management.