Ryan Denu

Education:

Research:

My research focuses on defining how epigenetic and transcriptional programs drive cellular plasticity in sarcoma and how these processes can be therapeutically targeted. I investigate how chromatin remodeling and lineage-inappropriate transcriptional networks enable sarcoma cells to transition between differentiated and dedifferentiated states, promoting tumor progression, immune evasion, and treatment resistance.

Using integrated multi-omic approaches—including single-cell profiling, epigenomic mapping, and functional genomics—I aim to identify key regulatory dependencies underlying these plastic states. My work centers on three major mechanisms. First, we examine transcription factor-driven plasticity. For example, we have identified that leiomyosarcomas rely on nuclear factor I (NFI) transcription factors to drive a mesenchymal cell state that is associated with more aggressive biology and adverse patient outcomes. Second, we interrogate epigenetic vulnerabilities created by chromatin regulator loss. This has focused on loss of ATRX in sarcoma, which drives chromatin remodeling and creates novel dependencies that we seek to exploit therapeutically. Third, we study signaling pathways that enforce dedifferentiation. For example, we have identified that YAP-TEAD signaling is important for driving dedifferentiation in liposarcoma.

Ultimately, my goal is to translate these mechanistic insights into biomarker-driven therapeutic strategies that constrain plasticity and improve outcomes for patients with sarcoma.