David Largaespada, PhD

Cancer functional genomics, insertional mutagenesis, transposons, Sleeping Beauty, CRISPR, Neurofibromatosis type 1 (NF1), pediatric cancer, brain tumors, sarcoma

Dr. Largaespada’s laboratory is focused on exploiting functional genomics and biotechnology to identify and target the genes and pathways that drive cancer. His group pioneered the use of the Sleeping Beauty (SB) transposon system for forward genetic screens in mouse models, enabling the discovery of cancer genes involved in sarcomas, hepatocellular carcinoma, gastrointestinal tract cancers, breast cancer, and especially NF1-associated tumors such as malignant peripheral nerve sheath tumors (MPNSTs). A central emphasis of this work is on identifying drivers of tumor initiation, metastasis, therapy resistance, and vulnerabilities that can be translated into therapeutic strategies.

The lab continues to advance SB-based mutagenesis, CRISPR/Cas9 genome editing, and single-cell technologies to identify cancer drivers and test rational drug combinations. This includes the creation of novel mouse models of NF1-deficient tumors and preclinical evaluation of emerging therapeutics, including MEK and HDAC inhibitors, as well as targeted drug combinations aimed at epigenetic vulnerabilities in PRC2-deficient MPNSTs and H3K27M gliomas. The group also integrates comparative genomic and proteomic analyses with functional screens to prioritize clinically relevant cancer genes.

Beyond gene discovery, Dr. Largaespada’s laboratory is committed to translational biotechnology development. The team has partnered in the creation of advanced nanocarriers for tumor-specific drug delivery and engineered viral and non-viral gene vectors to enhance therapeutic delivery. In parallel, the lab is pursuing adoptive cell therapy approaches, including CAR-T and CAR-NK engineering for solid tumors, and is applying SB mutagenesis to discover genetic modifications that improve the persistence and function of therapeutic immune cells in hostile tumor microenvironments.

Together, these efforts bridge cancer genetics, biotechnology innovation, and cell therapy development, with the goal of delivering next-generation therapies for NF1-associated tumors and other treatment-resistant cancers.