PROX1 is an Early Driver of AR Pathway Loss and Lineage Plasticity in Prostate Cancer

Lineage plasticity in prostate cancer is now recognized as a critical determinant of lethality. It represents a continuum, ranging from AR activity-low tumors to AR-null tumors that do not express a neuroendocrine prostate cancer (NEPC) program—referred to as double-negative prostate cancer (DNPC)—and fully AR-null NEPC tumors. Despite its importance, factors upregulated early in the process of lineage plasticity have yet to be identified. Identifying such factors is crucial for detecting tumors that are undergoing lineage plasticity or are at risk of developing it. Through integrative genomic analysis of metastatic castration-resistant prostate cancer patient tumors, patient-derived xenografts, and cell models, we found that PROX1 is upregulated early in the lineage plasticity continuum, particularly in AR activity-low tumors, and progressively increases in DNPC and NEPC tumors. Our functional studies demonstrated that PROX1 plays a pivotal role in NEPC, as its knockdown (KD) using lentiviral shRNA reduces the neuroendocrine phenotype, decreases cell proliferation, and increases apoptosis. In this dataset, we provide RNA-seq data from PROX1 KD in NEPC cells (NCI-H660), revealing key pathways altered by PROX1 suppression. These findings suggest that PROX1 is a promising target in NEPC treatment.