Transcriptional Regulation of Glioma Cell State Transitions and Microenviroment Interactions (360G-Wellcome-323976_Z_24_Z)

Glioblastoma is the most common and malignant primary brain tumour. It exhibits considerable transcriptional heterogeneity and marked plasticity, contributing to the failure of targeted therapies 2. Only 7 out of 100 patients survive for more than 5 years 1. Hence, it is a tumour of unmet clinical need. Recent integrated single-cell and muti-omic data point to a hierarchy of cell state identities, with a proliferative neural progenitor- like cell state (NPC-like) at the ‘top’ of this hierarchy. These datasets highlight candidate master regulators of the NPC-like state, including specific transcription activators and repressors. Among these, POU2AF2 has previously been implicated in cancer initiation and progression in small-cell lung cancer7, and SOX11 has established roles in embryonic and adult neurogenesis 6,10. In addition, the same datasets have identified putative ligand-receptor interactions between interferon-induced tumour-associated macrophages (TAMs) and NPC-like malignant cells, which promote cancer cell death. Given this, a pressing therapeutic rationale exists for exploring glioma cell state-specific vulnerabilities and exploiting cell state-specific interactions with the microenvironment. Specifically, we hope to induce apoptosis in NPC-like malignant states through interaction with interferon- TAMs.