Unraveling nonsense-mediated mRNA decay mechanisms in cancer

Our project delves into the multifaceted role of nonsense-mediated mRNA decay (NMD) in cancer, extending beyond its conventional function of degrading faulty mRNA transcripts. We hypothesize that understanding NMD's regulatory functions in cancer, particularly their interaction with the surveillance mechanisms of NMD, holds significant promise for illuminating cancer biology and predicting treatment responses. Leveraging extensive resources like the Cancer Genome Atlas (TCGA) and the Dependency Map (DepMap), our objectives encompass three specific aims. We will first explore how NMD's fine-tuning of gene expression relates to gene dependencies in various cancer types. Using NMD residual signatures, we will decode gene dependencies in cancer cell lines from DepMap and assess their predictive power in TCGA tumor samples. Next, we will identify regulatory genetic variants associated with NMD in cancer, distinct from premature termination codon (PTC)-causing variants, to understand their impact on NMD's surveillance strength. Our innovative statistical and computational models will evaluate NMD's quality control strength under different NMD-QTL contexts, aiming to identify individuals who might benefit most from NMD-inhibition-based therapies. Lastly, our research focuses on uncovering new NMD-modulatory factors and their interactions with cancer-driver genes. In summary, our project aims to make full use of existing multi-omics data in cancer research to accelerate discoveries regarding NMD regulation in cancer. By establishing connections between NMD regulation, gene dependencies, and regulatory genetic variants in cancer, we hope to provide novel insights beyond the scope of the original data collection efforts. These insights have the potential to guide the development of personalized cancer therapies, leveraging NMD's intricate mechanisms as a crucial post-transcriptional regulator. The statistical and computational methods we develop will not only advance our understanding of NMD in cancer but also have broader applicability to understanding other diseases. Project Number: 1R01CA301708-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Liang Chen | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $479,234 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 BBBT-M (84)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11319652