The Tao Wu Lab is a cancer epigenetics lab. Our long-term goal is to overcome the cancer therapeutic resistance. The field of cancer therapeutics has developed powerful approaches such as chemotherapy, molecularly targeted treatments, and immunotherapy. Although these therapies have significantly altered patient outcomes, anticancer therapeutic resistance remains the major challenge in achieving longer-lasting remission. In addition to the classical pathways adopted by neoplastic cells to achieve treatment resistance, altering epigenetic regulation has been increasingly recognized as an essential contributor. Moreover, the persistence of the cancer stem cell and tumor cell heterogeneity also contribute to the development of resistance. While the FDA has now approved several drugs that target the well-known epigenetic regulators or markers, the underlying molecular mechanisms that broadly govern cancer epigenetic dysregulation remain elusive.

With our discovery of a novel DNA methylation (N6-methyladenine, or 6mA) and a new ChIP-Seq approach (SMRT-ChIP) in the mammalian cell models, our lab will systematically investigate the epigenetic regulatory mechanisms underlying cancer treatment resistance. Based on the preliminary data, the DNA 6mA may be an "Achilles' heel" in the treatment of resistant cancer cells. The proposed research will examine how DNA 6mA and its regulators control the development of treatment resistance in cancer stem cell models. By combining single-molecule SMRT sequencing, improved single-cell sequencing, and optimized CRISPR/Cas9 screening approaches, we will explore new cancer dependencies that involve this novel DNA methylation and its regulators in different types of cancer. Our projects offer new opportunities for defining novel vulnerabilities and developing new strategies to overcome the therapeutic resistance in cancer treatment.