Ectopic Neuroligin Signaling in Pediatric Glioblastoma
Pediatric glioblastoma multiforme (pGBM) (AKA pediatric hemispheric high-grade glioma) is a malignant (WHO grade IV) tumor. It accounts for about 3% of primary brain tumors in children in the United States. The median survival of children with GBM ranges from 13 to 20 months, with the vast majority succumbing to the disease. Despite extensive research, we know very little about which and how human neural cells regulate pGBM cell propagation in the brain. Recently, we have found that GBM spheroids can be efficiently fused with organized-developing human brain tissue (organoids) generated from human induced pluripotent stem cell (iPSC) derived single neural rosettes (Hu-iPSC- SNR) to form tumor-organoid chimera. Interestingly, tumor cells survive and efficiently propagate in the tumor-organoid chimeras. In addition, we discovered that inhibitory neurons and GBM cells are likely to interact with each other in chimeras through a specific set of cell-to-cell adhesion molecules, Neuroligins and Neurexins, that are well-known for regulating synaptic communication between neurons in the brain. These results suggest that the Neuroligin-Neurexin-based cell-to-cell communication between inhibitory neurons and tumor cells may be involved in regulating tumor propagation in the brain.
Project Goal:
The goal of this project is to elucidate the cellular and molecular mechanisms involved in the regulation of pGBM propagation in the human brain. We hypothesize that abnormal Neuroligin-Neurexin signaling between inhibitory neurons and tumor cells in pGBM promotes tumor cell survival and growth. To test this hypothesis, we will investigate the communication between inhibitory neurons and tumor cells in tumor-organoid chimera and the roles of Neuroligins and Neurexins in regulating this communication. This study will advance our understanding of the cellular and molecular mechanisms involved in pGBM regulation and provide a novel preclinical platform to assess the safety and efficacy of anti-cancer therapies.
