ERG Orchestrates a Dedifferentiation–Senescence–Inflammation Triad in Prostate Cancer

Abstract ERG fusions occur in about 50% of prostate cancers and represent early somatic events that co-initiate tumorigenesis. Yet, the molecular programs unleashed by ERG at disease onset remain elusive. In this study, the inducible, temporally controlled expression of ERG enabled the accurate mapping of early ERG-driven processes associated with an apparent decrease in cell fitness across a panel of prostate cells. We observed that ERG triggers senescence and epithelial–mesenchymal transition (EMT), generating distinct cellular states in which EMT and senescence coexist in the same cell or occur independently. ERG-mediated activation of canonical and noncanonical TGFβ signaling differentially regulates EMT and senescence markers. Moreover, ERG drives context-dependent changes in cell identity and promotes an intermediate basal–luminal cell population with stem cell gene expression. Notably, p53 loss enhances ERG-driven expression of cell plasticity markers without affecting senescence. Transcriptomic investigation of ERG-expressing epithelial cells revealed activation of inflammatory signals. Conditioned medium experiments demonstrated paracrine-mediated inflammation in epithelial ERG-negative, stromal, and myeloid cells. Consistently, patient-derived expression data from five independent cohorts and 2,048 men showed activation of TNFA–NFKB and TGFβ signaling in ERG-rearranged tumors. Furthermore, deconvolution analysis indicated a higher infiltration of inflammatory macrophages in ERG-positive tumors. Altogether, we uncovered a previously unrecognized triad of ERG-driven processes—dedifferentiation, senescence, and inflammation—that may underpin its oncogenic potential and shape prostate cancer initiation and therapeutic response. Implications: Temporal control of ERG expression in prostate cells enabled accurate mapping of ERG-driven processes, identifying dedifferentiation, senescence, and inflammation as candidate contributors to ERG-dependent tumorigenesis and therapeutic response.