Identifying mechanisms of structural variant-induced gene activation in glioma

Genomic instability is a hallmark of cancer that can result in large structural variants including deletions, duplications, inversions, and translocations. Structural variants lead to oncogenesis through a variety of mechanisms, including amplification of oncogenes, deletion or tumor suppressors, and alteration of gene expression. Certain cancers like gliomas exhibit high rates of structural variation, contributing to the transcriptional and cellular heterogeneity that circumvents current standards of care. An emerging mechanism of how structural variants contribute to oncogenesis is a process known as enhancer hijacking, wherein rearranged genes become regulated by non-native enhancers. Despite a growing understanding of the roles for enhancer hijacking in cancer genomes, the features of structural variants that enable enhancer hijacking are largely unknown. To address this gap in knowledge, the proposed research seeks to identify regulators of enhancer hijacking events, with the goal of understanding the mechanisms of how structural variants contribute to glioma progression and relapse. Using engineered models of enhancer hijacking, preliminary CRISPR knockout screens identified subunits of the Cohesin and BAF complexes as trans-acting factors that facilitate the activation of rearranged genes. To gain a deeper understanding of the mechanism by which Cohesin and BAF mediate enhancer hijacking events, the proposed work will utilize protein depletion experiments against various subunits implicated by the screens, followed by rescue experiments and protein engineering. To extend these findings to structural variants observed in the glioma patient population, the roles of Cohesin and BAF will also be tested in glioma cell lines which do or do not exhibit structural rearrangements of the frequently observed driver EGFR. Finally, the functional effects of a patient-derived CDK4 translocation and its dependence on enhancer hijacking will be assessed through the generation of in vivo models using a pioneering CRISPR/Cas9 translocation engineering approach. Ultimately, this work will not only elucidate the molecular determinants of enhancer hijacking events but is also expected to yield important insights regarding the role of structural variants in glioma progression that can be clinically translatable to risk determination, patient stratification, and treatment. The Dixon and Furnari laboratories have established exceptionally productive and innovative research programs that will strongly support the goals of this proposal. The cutting-edge genomics techniques and engineering approaches established in the Dixon lab will be complemented by the Furnari lab’s modeling expertise in the glioma field. On a mentoring level, the Dixon and Furnari labs represent two highly successful career trajectories in academia from which the trainee will glean critical skills for establishing scientific independence. The graduate training described in this proposal will bolster the scientific rigor and confidence of the trainee to ultimately foster the necessary skills and perspectives to become an independent scientist. Project Number: 1F31CA301889-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Tula Keal | Institution: SALK INSTITUTE FOR BIOLOGICAL STUDIES, La Jolla, CA | Award Amount: $46,939 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F09A-R (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11318066