The Lazarus Effect in Prostate Cancer: a Secondary Analysis of Prostate Cancer Transcriptomic Datasets

Abstract

Castration-resistant prostate cancer (CRPC) emerges after an initial period of tumor regression induced by androgen deprivation therapy (ADT), a paradoxical reappearance termed the Lazarus effect. Two cellular programs have been proposed to underlie this phenomenon: the senescence-associated secretory phenotype (SASP) and the diapause program. This study examines which program governs the shrunken phase (S-PC) and subsequent CRPC emergence through secondary analysis of three independent human transcriptomic datasets. S-PC-specific gene signatures were gen- erated from a CRPC mouse model (GSE208321) using differential expression analysis, classified into SASP (108 genes) and Diapause (106 genes) categories, and converted to human orthologs. Single-sample gene set enrichment analysis (ssGSEA) was applied to patient biopsies (GSE111177), a longitudinal series of androgen-deprived LNCaP cell lines (GSE8702), and an enzalutamide resistance model (GSE150807). Overall, the analysis of these datasets supports a model in which the diapause transcriptional program, rather than SASP, is the primary cellular mechanism underlying the con- tractile phase and recurrence of CRPC. These findings have potential implications for therapeutic interventions in CRPC persistence by identifying diapause-associated factors as candidate targets for disrupting dormancy that mediates the Lazarus effect in prostate cancer.