Abstract 3310: Regulation of reprogramming factors by c-Met signaling in glioblastoma stem cells

Abstract

Abstract Reprogramming transcription factors such as Sox2, c-Myc, Klf4, Oct4 and Nanog have an essential role in sustaining the growth and self-renewal of embryonic stem cells. Forced expression of these reprogramming factors can reprogram differentiated somatic cells into pluripotent stem cells. Reprogramming factor overexpression has also been found in human cancer stem-like cells including glioblastoma stem cells (GBM SCs). This suggests that reprogramming factors support the self-renewing and tumor-initiating phenotype of cancer stem cells. Hence, the molecular signaling pathways that regulate reprogramming factor and their support of the cancer stem-like phenotype in GBM and other solid tumors are of considerable interest. We recently found that the tyrosine kinase c-Met oncogene up-regulates a network of reprogramming factors consisting of Oct4. Sox2, Klf4, c-Myc and Nanog in GBM-derived neurospheres that are enriched in GBM SCs. Reprogramming factor induction by c-Met was observed under serum-free culture conditions that support neurosphere-formation and in cells that were pre-differentiated in serum-containing medium. Using flow cytometry and quantitative reverse transcription-PCR, we also found that GBM neurosphere cell subpopulations expressing c-Met at high levels also express high levels of Nanog and Sox2 in comparison to low c-Met expressing cells. Using specific pharmacological inhibitors of PI(3)kinase (LY294002, wortmannin), MAPkinase (PD98059, U0126), and Stat3 (Stattic, Janus Kinase JSI-124), we found that c-Met signaling regulates reprogramming factors mainly via two parallel pathways: the Jak-Stat3 and PI(3)K-Akt pathways. Inhibiting Oct4 induction abrogated the capacity of c-Met to induce Sox2, c-Myc, and Nanog but not KLF4 expression. Inhibiting Nanog induction significantly inhibited (84% inhibition) the capacity of c-Met signaling to stimulate GBM SC self renewal as measured by neurosphere formation and Edu incorporation, 84% and 61% inhibition, respectively. Together, these findings indicate that c-Met signaling upregulates an Oct4- and Nanog-dependent reprogramming factor network that supports GBM SCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3310. doi:10.1158/1538-7445.AM2011-3310