Increasing Cancer Stemness Drives Prostate Cancer Progression, Plasticity, Therapy Resistance and Poor Patient Survival.

Background: Cancer progression is often accompanied by dedifferentiation and acquisition of stem cell-like properties (stemness). In prostate cancer (PCa), lineage plasticity and therapy resistance remain major clinical challenges, yet a unified quantitative transcriptomic framework connecting stemness, androgen receptor (AR) signaling, castration resistance, and disease progression across the PCa continuum is lacking. Methods: We integrated 87,339 transcriptomic profiles from 33 preclinical and clinical datasets spanning the PCa continuum from normal prostate and treatment-naïve primary PCa (Pri-PCa) to PCa treated with neoadjuvant ADT (nADT) and metastatic castration-resistant PCa (mCRPC), with single-cell RNA-seq analyses encompassing 115,197 cells. Cancer stemness was quantified using a transcriptome-derived mRNA-based Stemness Index (mRNAsi; hereafter Stemness), and a 12-gene PCa-Stem signature was developed to capture PCa-specific stemness. Stemness, PCa-Stem, canonical AR activity (c_AR-A), castration-reprogrammed AR activity (cr_AR-A), Results: The Stemness score and c_AR-A increased concordantly during early prostate tumorigenesis but diverged with PCa progression: as Gleason grade increased, c_AR-A declined while Stemness continually increased. mCRPC exhibited the highest Stemness and lowest c_AR-A, a pattern recapitulated in Conclusions: Cancer Stemness quantitatively captures PCa aggressiveness, lineage plasticity, treatment resistance, disease progression, and poor patient survival. cr_AR-A,