Though best known as the indispensable intermediate between DNA and proteins, RNA is now appreciated to have a wide variety of other cellular functions. Among them, RNA processing (e.g. capping, splicing, base modifications, degradation, etc.) have increasingly been appreciated to regulate normal physiology, to become deranged in pathologies such as cancer and immune dysfunction, and most excitingly, to be therapeutically actionable.
Our laboratory seeks to understand RNA processing in health and disease. We focus on studying how normal and altered RNA processing (e.g. splicing) impact hematopoiesis, immune function, cancer, and anti-cancer immunity. The ultimate goal is to better understand how RNA processing drives pathologic processes, and to develop novel RNA-based therapies for cancer and immune dysfunction.
A key step in forming mature, protein-coding messenger RNA (mRNA) in eukaryotes is splicing, the process of removing introns and splicing exons together. Alterative splicing generates multiple proteins from a single genomic locus, and serves as a key regulator of cell and tissue physiology. Correspondingly, alterations of RNA splicing and the downstream consequences have been prominently studied in the nervous system and in hematologic disorders (myeloid cancers and chronic lymphocytic leukemia) where recurrent mutations of splicing factor genes act as clear oncogenic drivers. FDA-approved drugs exist for neurologic disorders with splicing alterations, and splicing modulator drugs are also being actively studied in clinical trials for a variety of hematologic cancers.
Beyond just these two domains however, aberrant RNA splicing also appears to regulate the pathophysiology of a variety of solid tumors. In addition, there is an increasing body of evidence that RNA processing and its alterations can regulate immune function and dysfunction.
Current Projects.
We employ multi-disciplinary approaches, with a focus on clinically-relevant models, to understand how aberrant RNA processing regulates the pathogenesis of cancer, and how RNA processing regulates immunity and hematopoiesis. Current projects in the lab include:
Understanding the role of RNA splicing in T cell development and function
Understanding how tumors with splicing alterations modulate the immune system
Therapeutic targeting of RNA splicing-derived neoantigens for cancer immunotherapy