The clinical inefficacy of glioma therapy can be, in part, attributed to the persistence of a disseminated subpopulation of glioma cells that survive treatment, only to disperse and repopulate the brain. These glioma stem cells (GSCs) are potent and resilient - capable of propagating the tumor from a very low titer, but also more resistant to radiation and chemotherapy. Mounting evidence suggests a facilitative relationship between gliomas and the subventricular zone (SVZ), a stem cell niche that supports migration of newborn neurons in humans. Although glioma contact with the SVZ has been offered as evidence for a stem cell origin of the tumor, this proposal will test an alternative interpretation- that the SVZ is a preferred migratory route for tumor invasion and a reservoir for GSCs. In previous work, we identified the human SVZ 'gap'layer that lies under the ependyma and demonstrated this to be a major corridor for migrating young neurons during infancy. Preliminary data suggests that the human gap layer is hypocellular in adults, but retains high levels of pro-migratory ligands potentially co-opted by gliomas during subventricular spread. Using a glioma cell labeling agent, 5-aminolevulinic acid (5-ALA), that is administered to patients prior to tumor resection, we have determined that the human SVZ is highly-enriched for infiltrating GSCs, even when diagnostic imaging shows no evidence of disease. We hypothesize that GSCs preferentially home to the human SVZ from the primary tumor mass and are vulnerable to SVZ-directed therapy. Using intraoperative tissue, we propose to characterize human glioma and GSC homing to the SVZ, determine the effects of SVZ-directed radiation and chemotherapy, and identify new, targetable signaling pathways to disrupt this niche. In adapting our system for human SVZ analysis to investigate 5-ALA-treated glioma patients, the proposed work will define patterns of glioma and GSC infiltration of the human SVZ, evaluate how existing therapies disrupt this migratory corridor and GSC reservoir, and identify molecular targets that drive subventricular spread and GSC homing.
Gliomas are highly invasive cancers and impossible to surgically cure. In this study, we use human brain tissue to determine how glioma stem cells migrate undetected and co-opt a normal neural stem cell region, the subventricular zone (SVZ), to support their own growth and dispersal. In identifying the molecular mechanisms enabling this behavior and characterizing the response of SVZ-invasive glioma stem cells to radiation and chemotherapy, the proposed work will identify new strategies, using both conventional and molecularly-targeted approaches, to neutralize this evasive tumor population.
|Kusne, Yael; Carrera-Silva, Eugenio A; Perry, Anthony S et al. (2014) Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNF? in glioblastoma. Sci Signal 7:ra75|
|Liu, Jonathan T C; Meza, Daphne; Sanai, Nader (2014) Trends in fluorescence image-guided surgery for gliomas. Neurosurgery 75:61-71|
|Tang, Zhiwei; Gan, Yan; Liu, Qiang et al. (2014) CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. J Neuroinflammation 11:26|