Decoding Long Noncoding RNA Networks in Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer

Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in the management of metastatic castration-resistant prostate cancer (mCRPC). Emerging evidence highlights lineage plasticity, the ability of tumor cells to transition from an AR-dependent luminal state to alternative, AR-independent phenotypes, as a key driver of therapy resistance. To date, most genomic and epigenetic alterations implicated in driving lineage plasticity and therapeutic resistance involve protein-coding genes. However, the non-coding regulatory mechanisms that enable this phenotypic shift remain poorly defined. Through an unbiased genome-wide CRISPR interference (CRISPRi) screen targeting ~10,000 long non-coding RNAs (lncRNAs), I identified multiple previously uncharacterized candidate lncRNAs, including Radiation sensitive 21 antisense (RAD21-AS), Colorectal Neoplasia Differentially Expressed (CRNDE), Small Nucleolar RNA Host Gene 15 (SNHG15), and PSMG3-AS, which were prioritized for further study. Specifically, CRNDE stood out as a lead candidate with significant clinical relevance, whose deletion confers resistance to AR-targeted therapies both in vitro and in vivo. My preliminary and mechanistic results revealed that CRNDE deletion could potentially induce therapy resistance by upregulating Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2), a collagen-modifying enzyme that elevates intracellular succinate levels and activates a neuroendocrine-like transcriptional program. Based on the preliminary data, I will test the central hypothesis that frequently observed lncRNA alterations contribute to lineage plasticity and resistance to AR-targeted therapies in mCRPC, with CRNDE-deficiency promoting a PLOD2-driven plastic and resistant state. The overall objective of this study is to comprehensively elucidate the functions and molecular mechanisms of how lncRNAs drive lineage plasticity and AR-targeted therapies resistance, with the intent to develop innovative therapeutic approaches to overcome resistance. To test the hypothesis, I will first assess the role of the top candidate lncRNAs identified from my CRISPRi library screening, including CRNDE, RAD21-AS, SNHG15, and PSMG3-AS, in mediating lineage plasticity and AR- targeted therapy resistance in various clinical relevant prostate cancer (PCa) models (Aim 1, K99). In Aim 2 (R00), I will define the roles of CRNDE in lineage plasticity and AR therapy response in PCa. Finally, in Aim 3 (R00), I will elucidate the molecular mechanism through which CRNDE-deficiency conferred lineage plasticity and AR therapy resistance. This research will address critical gaps in understanding how lncRNAs drive lineage plasticity and resistance, and identify novel therapeutic targets to improve patient outcomes with resistant PCa. Moreover, this work will establish a distinct research niche at the intersection of non-coding RNA biology, lineage plasticity, and therapy resistance, supporting my transition to an independent academic career. I have assembled an expert mentoring and advisory team, led by a prostate cancer expert Dr. Ping Mu and a non-coding RNA pioneer Dr. Haifan Lin, at Yale School of Medicine to guide my training and transition to independence. Project Number: 1K99CA312735-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Yaru Xu | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $115,076 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 CDPT-N (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11357789