MBD4 Driven AR Reprogramming and Luminal Lineage Specification in Prostate Cancer

/Abstract CANDIDATE: I am a postdoctoral fellow in Dr. Christopher Barbieri’s laboratory at Weill Cornell Medicine, where I investigate the molecular determinants of prostate cancer progression. My PhD training at Tianjin Medical University focused on androgen receptor (AR) signaling and therapy resistance. At Weill Cornell, I have advanced my expertise in high-throughput genomic and epigenomic analyses. My career development plan focuses on acquiring skills in single-cell transcriptomics and epigenomic profiling to prepare for an independent faculty position in translational prostate cancer research. RESEARCH: In the normal prostate, AR signaling maintains luminal identity and drives growth-suppressive programs; however, during tumorigenesis, AR is co- opted into oncogenic programs that drive malignancy. Preliminary data from my genome-wide approach with an unbiased CRISPR-screen have identified MBD4, a methyl-CpG binding protein, as a pivotal regulator of these opposing AR programs. Loss of MBD4 redirects AR activity away from growth suppression toward oncogenic programs by altering FOXA1 binding. In this proposal, I will (Aim 1) define the molecular mechanisms by which MBD4 loss modulates AR function through cell-based assays, organoids, and in vivo models; (Aim 2) elucidate MBD4’s role in maintaining prostate luminal specification using single-cell transcriptomic and functional studies; and (Aim 3) characterize the temporal dynamics of MBD4 downregulation during the transition to prostate cancer through integrated single-cell RNA and targeted methylation profiling. These studies will test whether MBD4 functions as a molecular switch controlling AR’s dual programs and will identify novel therapeutic strategies for precision AR-targeted therapy. ENVIRONMENT: Weill Cornell Medicine is internationally recognized for its excellence in prostate cancer research and provides cutting-edge genomic, epigenomic, and single-cell analysis platforms. Because of the bioinformatics relevance of the project, I have included Dr. Andrea Sboner as a co- mentor; his expertise in computational genomics and multi-omics analysis will be essential for guiding the study’s bioinformatics aspects. My advisory committee also includes Dr. Yu Chen from Memorial Sloan Kettering Cancer Center, whose expertise in prostate cancer organoid modeling and epigenetic regulation provides invaluable insight, and Dr. David Rickman, a leading authority in cellular transitions and lineage plasticity. The combined expertise of my mentors and advisors, along with the state-of-the-art resources at Weill Cornell Medicine, will strongly support my successful transition to an independent research career. Project Number: 1K99CA312863-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Xuanrong Chen | Institution: WEILL MEDICAL COLL OF CORNELL UNIV, NEW YORK, NY | Award Amount: $151,618 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 CDPT-N (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11351787