Quiescent Human Glioblastoma Stem Cells Mediate Tumor Initiation, Expansion, and Recurrence Following Chemotherapy

We test the hypothesis that human glioblastoma harbors quiescent cancer stem cells that evade anti-proliferative therapies. Functional characterization of spontaneous glioblastomas from genetically engineered mice reveals essential quiescent stem-like cells that can be directly isolated from tumors. A derived novel quiescent cancer stem cell specific gene expression signature is enriched in pre-formed patient xenograft single cell clusters that lack proliferative gene expression. A refined human 118-gene signature is preserved in quiescent single cell populations from primary and recurrent human glioblastomas. The signature conserved F3 cell surface receptor identifies quiescent tumor cells by antibody immunohistochemistry. F3 antibody sorted quiescent glioblastoma cells exhibit stem cell gene expression, enhanced self-renewal in culture, mediate tumor initiation, serial transplantation, and reconstitute tumor heterogeneity. Upon chemotherapy, the spared cancer stem cell pool becomes activated and accelerates transition to proliferation. These results help explain conventional treatment failure and lay a conceptual framework for alternative therapies.