Brain cancer is rarely curative and urgently needs novel transformative treatments. Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is also among the most heterogeneous, aggressive, and lethal tumors. Despite maximum treatment, nearly all GBM patients experience tumor regrowth within 7-9 months of diagnosis, and recurrent tumors are currently untreatable. To better understand and ultimately conquer GBM, it is critical to identify different mechanisms and their coordination that drive dynamic changes in a patient’s tumor and its surrounding tissue environment. For example, alternative splicing (AS) is a widely acting gene regulatory mechanism that impacts almost all human genes. It can regulate every hallmark of cancer, providing opportunities to uncover new mechanisms and therapeutic targets. We will develop innovative, scalable, and cost-effective single-cell profiling, genetics, and bioinformatics platforms for the timely characterization of unique patient GBM samples and patient-derived models. Our goal is to systematically reveal how AS impacts and coordinates with other regulatory mechanisms to control GBM heterogeneity, plasticity, and progression. This will uncover a potentially huge yet unexplored reservoir of new biomarkers and therapeutic targets. Moreover, our integrated, out-of-the-box approach is highly translatable to investigate diverse brain cancers and disorders, contributing to basic and translational cancer research.
