Abstract 3335: The potential role of lateral inhibition in the maintenance of glioblastoma cancer stem cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Glioblastoma (GBM) is a malignant cancer of the central nervous system. Tumor cells are highly resistant to conventional therapies and tumors always recur. Cancer stem cells are thought to be critical for long-term growth and therapeutic resistance of GBM. It is therefore important to understand the signaling mechanisms maintaining GBM cancer stem cells. Notch is known to be an important signaling pathway during neural development, and can promote the maintenance of stem and progenitor cells via the process of lateral inhibition. Lateral inhibition is a contact-dependent signaling mechanism by which some cells within a field remain stem-like while others differentiate. In normal development, Notch ligands initiate this process by binding to the receptor on an adjacent cell, signaling to this neighbor to remain undifferentiated. Although Notch is known to be a critical player in the maintenance of stem-like cancer cells in various tumor types, including GBM, it is not known if the mechanism of lateral inhibition is also conserved in neural cancer stem cells. To test this hypothesis, we engineered a model system where isogenic cells expressing low and high levels of the Jag1 ligand are co-cultured followed by flow-based separation and determination of Notch pathway activity in each respective population. These experiments suggest that lateral inhibition is conserved in GBM. In the GBM neurosphere lines HSR-GBM1 and 040821, co-culture induced expression of Notch targets Hes5 and Hey1 in Jag1-low “signal receiving” cells and inhibited expression of these targets in Jag1-overexpressing “signal sending” isogenic cells. Preliminary experiments suggest that the ligand intracellular domain (ICD) is involved in this process. Our data suggest conservation of a developmental mechanism regulating Notch activation in cancer, and may affect our understanding of how to treat Notch-dependent tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3335. doi:1538-7445.AM2012-3335