Regulation of glioblastoma cells by GABAergic neurons in human organoid-tumor chimeras

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM, WHO Grade IV glioma) is one of the most common and deadliest primary brain tumors that affects both children and adults. GBM is associated with significantly elevated mortality, and there are no effective therapies available for patients despite many previous clinical trials. It is believed that a better understanding of the cell types and factors regulating GBM cell properties in the brain could provide novel insights into the pathology and reveal new therapeutic targets for treating GBM patients. The main goal of this R21 proposal is to elucidate the role of human GABAergic neurons in regulating the proliferation and survival of GBM cells in the brain using an innovative co-culture approach of human GBM spheroids and human induced pluripotent stem cell (iPSC)-derived telencephalic organoids (organoid-GBM chimera). To achieve this goal, we will use the most advanced neuroscience tools and techniques, including human stem cell-derived brain organoids, optogenetics, rabies virus tracing, and single-cell RNA sequencing, to characterize the communication between GABAergic neurons and tumor cells in organoid-GBM chimera and the effects of this communication on tumor cell survival and proliferation. Our specific hypothesis is that GABAergic neurons form functional synapses with tumor cells in GBM-organoid chimeras to promote tumor cell proliferation or survival via GABA-mediated depolarization of tumor cells. The specific aims to test this hypothesis are (1) to determine whether GABAergic neurons establish functional synapses with GBM cells to regulate tumor growth and survival and (2) to determine the role of trans-synaptic signaling proteins in regulating tumor growth and survival. Overall, we expect that this study will advance our understanding of the cellular and molecular mechanisms involved in the regulation of GBM cell properties in the human brain and provide a novel framework for studying the interactions of human brain tumors with human neurons in a human brain-like environment.