CNSC-84. GLIOBLASTOMA HIJACKS NEURONAL MECHANISMS TO EVADE APOPTOSIS

Abstract Infiltration and integration of cancer cells into normal brain structures is a hallmark of glioblastoma (GBM) and contributes to both the high recurrence rates and the limited efficacy of current therapies. Recent studies have shown that glioma cells can functionally integrate into neuronal circuits, enabling neuronal activity to directly promote tumor cell proliferation. However, the underlying molecular mechanisms responsible for neuron-glioma circuits driving therapeutic resistance remain unclear. Here, we uncover that glioma-neuronal integration can alter the ability of GBM to evade cell death. Specifically, we find that the brain microenvironment modulates the intrinsic apoptotic machinery of GBM cells through direct cell-cell contact and alters their calcium signaling dynamics. We hypothesize that neuron-induced calcium modulation mediates the expression or activity of key apoptosis proteins, ultimately suppressing intrinsic cell death pathways. Collectively, by defining the molecular underpinnings of this neuron-mediated resistance to apoptosis could reveal novel, microenvironment-specific vulnerabilities that inform the next generation of GBM therapies.