It has been proposed that rare, treatment-resistant neoplastic stem cells are critical for long-term tumor growth. Normal stem cells require signals from a stromal """"""""niche"""""""" to self-renew. However, the role of such niche-signals in regulating cancer stem cells (CSCs) is largely unknown. The Notch signaling pathway regulates neural stem cell self-renewal, and recent studies found that CSCs in glioblastoma (GBM) have elevated Notch activity. Our recent data shows that Notch pathway inhibition by gamma-secretase inhibitors reduced CD133 expression and reduces glioblastoma neurosphere propagation both in vitro and in vivo. In the current application, we propose using GBM neurosphere cultures to determine the mechanism and niche-dependence of Notch activation in CSCs. Specifically, we will seek to determine if Notch activation is driven by juxtacrine signaling between tumor cells replicating the classical process of lateral inhibition, by stromal niche signals, or both.
Aim1 - Determine if activation of Notch in CSCs is mediated by juxtacrine signaling via Notch ligands expressed in better-differentiated tumor cells.
Aim2 - Define if the endothelial cells function as CSC niche by providing Notch ligands to CSCs in glioblastoma.
Aim3 - Determine if regulation of Notch activity in endothelial cells contributes to the non-functional microvascular proliferation in GBM. Answering these questions will facilitate the development of novel therapies and enhance our understanding of cancer stem cell biology.
Glioblastoma is the most malignant brain tumor in adult with no successful treatment during the past thirty years. The goal of this proposal is to understand how an important tumor micro-environment (cancer stem cell niche) regulates glioblastoma initiating cells in order to develop a novel therapeutic strategy for this deadly disease.
|Thompson, Eric M; Hielscher, Thomas; Bouffet, Eric et al. (2016) Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis. Lancet Oncol 17:484-95|
|Wang, Anthony C; Owen, John H; Abuzeid, Waleed M et al. (2016) STAT3 Inhibition as a Therapeutic Strategy for Chordoma. J Neurol Surg B Skull Base 77:510-520|
|Fan, Xing (2016) Î³-Secretase inhibitor-resistant glioblastoma stem cells require RBPJ to propagate. J Clin Invest 126:2415-8|
|Kahlert, Ulf D; Cheng, Menglin; Koch, Katharina et al. (2016) Alterations in cellular metabolome after pharmacological inhibition of Notch in glioblastoma cells. Int J Cancer 138:1246-55|
|Ramaswamy, Vijay; Hielscher, Thomas; Mack, Stephen C et al. (2016) Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 34:2468-77|
|Lim, Kah Jing; Brandt, William D; Heth, Jason A et al. (2015) Lateral inhibition of Notch signaling in neoplastic cells. Oncotarget 6:1666-77|
|Nie, Song; Gurrea, Mikel; Zhu, Jianhui et al. (2015) Tenascin-C: a novel candidate marker for cancer stem cells in glioblastoma identified by tissue microarrays. J Proteome Res 14:814-22|
|Mack, S C; Witt, H; Piro, R M et al. (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506:445-50|
|Spence, Tara; Sin-Chan, Patrick; Picard, Daniel et al. (2014) CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol 128:291-303|
|Baxter, Patricia A; Lin, Qi; Mao, Hua et al. (2014) Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes. Acta Neuropathol Commun 2:160|
Showing the most recent 10 out of 20 publications