Chromatin Disruption in Liver Cancer
Liver cancer is the third leading cause of cancer death worldwide, and hepatocellular carcinoma (HCC) accounts for most cases. Its incidence continues to rise, driven by viral hepatitis, metabolic dysfunction-associated steatohepatitis, and alcohol-related liver disease. Immune checkpoint inhibitors are now standard first-line therapy for advanced disease, but fewer than a third of patients respond and durable benefit is uncommon. Work on why has concentrated on the immune compartment. We study how the chromatin state of the tumor cell controls whether the immune system recognizes and kills it.
Chromatin regulators are among the most frequently mutated genes in HCC. The BAF form of the SWI/SNF remodeling complex alone is disrupted in about one in five liver tumors, a large genetic subset with no targeted therapy. We are studying the idea that altered BAF function in these tumor cells creates dependent chromatin states that can be targeted.
We are identifying the chromatin regulators that BAF-mutant liver tumors depend on to maintain these altered states, and testing whether removing them improve therapy responses. To keep the tumor and immune system together, we pair pooled, epigenome-focused CRISPR screens in immunocompetent orthotopic liver tumors with T-cell killing assays in BAF-mutant liver cancer lines. We want to find chromatin regulators whose loss reprograms immune-response pathways and to nominate combinations that could make immunotherapy work in a subtype of liver cancer that has few options.
Key Publications
- Dzama-Karels M, Sokolowski M, Kuhlers P, Brinkman JA, Morris JP 4th, Raab JR. Menin-MLL1 complex cooperates with NF-Y to promote hepatocellular carcinoma survival. Cell Reports (2025). 10.1016/j.celrep.2025.116619
- Brinkman JA, Dzama-Karels M, Bucklan M, Manner CJ, Sokolowski M, Raab JR. Loss of cBAF complex confers sorafenib resistance in liver cancer. bioRxiv (2026). 10.64898/2026.06.11.731725
- Nenad WC, Kuhlers P, Sturgill IR, Biju I, Bucklan M, Hernandez L, Zhu LC, Hoadley K, Raab J. BAP1 deletion in hepatocytes primes an inflammatory transcriptional response. bioRxiv (2025). 10.1101/2025.10.31.685807
- Sturgill IR, Raab JR, Hoadley KA. Expanded detection and impact of BAP1 alterations in cancer. NAR Cancer (2024). 10.1093/narcan/zcae045