Decoding Long Noncoding RNA Networks in Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer
openNCI - National Cancer Institute
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.
Up to $143K
health research