Grant: Project Grant

Adult brain tumors urgently need novel treatments as current therapies are rarely curative and provide poor survival benefits. Glioblastoma (GBM) is the most common primary brain tumor in adults with devastating neurological symptoms. It is also the most aggressive and lethal. Despite current treatment efforts, tumor re-growth is inevitable in GBM patients. Understanding mechanisms that drive rapid changes and dynamic interactions between a patient's tumor and its surrounding tissue environment is a key aspect of conquering GBM. Alternative splicing (AS) represents a widely acting gene regulatory mechanism, which greatly expands the protein repertoire in the cell such that a single gene can code for multiple protein products. Almost all human genes are alternatively spliced. AS can impact every hallmark of cancer, providing opportunities to uncover new mechanisms and therapeutic targets. Our proposed research aims to establish innovative technology platforms to discover and characterize AS regulation and its coordination with other gene regulatory mechanisms underlying GBM biology. Leveraging the power of systematic experimental and computational approaches, together with unique patient GBM and disease model studies, we will illustrate how GBM evolves in time and space to impact disease progression, therapy response, and relapse at the level of single cells. Together, our study will link multilevel genetic information to provide in-depth mechanistic insights and discover novel GBM therapeutics. Moreover, the framework and methods we built are highly translatable to investigate diverse hard-to-treat cancers, facilitating the development of a new generation of splicing-directed therapeutic strategies.