The role of genetic and epigenetic variation in the progression of IDH mutant gliomas

/Abstract The candidate for this K22 NCI Transition Career Development Award is Dr. Jingyi Wu, an Instructor in Pathology at Dana-Farber Cancer Institute, Harvard Medical School, and the Broad Institute. This award focuses on Dr. Wu’s long-term objective of becoming an independent investigator studying cancer epigenetics. Epigenetics is the fundamental mechanism that enforces the transcriptional programs and drives cellular phenotypes. Epigenetic regulation pathways are frequently altered in cancer, allowing transitions of cell states to acquire various fitness advantages. Building on Dr. Wu’s previous work, the enclosed application seeks to test the hypothesis that epigenetic alterations render tumors the plasticity to switch cell states upon genetic variation or drug treatment. The application presents preliminary data suggesting plasticity and cell state switching during the progression of IDH mutant gliomas. It also identifies a candidate genetic event and epigenetic perturbation that potentially drives cell state switching. The specific aims of this application will 1) further confirm the role of genetic and epigenetic variation in cell state switching and 2) identify the underlying mechanisms by which genetic and epigenetic variation drive cell state switching. The results of the proposed studies should reveal new therapeutic targets for IDH mutant gliomas. The application will leverage cutting-edge single-cell genomics and epigenetic assays, as well as advanced cell culture engineering and organoid disease models. This is a perfect extension of Dr. Wu's published and ongoing work, where she developed new single-cell genomics tools and applied them to other brain tumor models, including glioblastoma. Dr. Wu has access to all the resources at DFCI, HMS and Broad Institute for developing her leadership to become an independent investigator. She has also built a network for mentorship to ensure that she can achieve her 3 long-term career goals 1) address important and fundamental questions in cancer research, 2) mentor junior scientists, 3) build a collaborative community within the cancer research field. Project Number: 1K22CA285824-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: JINGYI WU | Institution: BETH ISRAEL DEACONESS MEDICAL CENTER, BOSTON, MA | Award Amount: $169,884 | Activity Code: K22 | Study Section: Special Emphasis Panel[ZCA1 RTRB-R (O1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/10784408