CB-07 * DISTINCT RADIATION RESPONSE OF SLOW-DIVIDING CANCER STEM CELLS

Abstract

Glioblastoma, the most frequent primary malignancy of the central nervous system, is almost universally fatal despite aggressive therapies, such as surgical resection, adjuvant radiation and chemotherapy, which remain largely palliative. With increasing evidence showing that glioblastoma cancer stem cells play an important role in tumor escape from conventional therapies and disease recurrence, the targeting of cancer stem cells with different therapeutic strategies provides new avenues of research and confidence for better outcomes. We have previously shown that isolating slow-dividing cells from glioblastoma enriches for a population with cancer stem cell properties. Here, we demonstrate that these slow-dividing cancer stem cells are more invasive and more tolerant to chemotherapy than the rest of the tumor population. Surprisingly, slow-proliferating cells are initially more sensitive to radiation damage. We find a significant overlap between the slow-proliferating compartment and expression of the transcription factor ZEB1, which we have recently identified as a master regulator of stemness and chemoresistance in glioblastoma. Consequently, ZEB1-positive cells also exhibit greater radiosensitivity. Slow proliferating, ZEB1-positive cells accumulate genomic aberrations correlated with retention in the G2/M phase of the cell cycle, rendering these cells more sensitive to radiation damage. However, from this specific subpopulation, a fraction of cells that survive irradiation rebound with a proliferative burst that may contribute to recurrence of more aggressive tumors. This distinct effect of radiation on cancer stem cells points to a previously underappreciated heterogeneity within the cancer stem cell compartment and may open up new avenues of studying and targeting specific cancer stem cell sub-populations.