ERG orchestrates a dedifferentiation-senescence-inflammation triad in prostate cancer

ERG fusions occur in about 50% of prostate cancers (PCa) and represent early somatic events that co-initiate tumorigenesis. Yet, the molecular programs unleashed by ERG at disease onset remain elusive. Here, 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 non-canonical TGF beta 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 5 independent cohorts and 2,048 men showed activation of TNFA-NFKB and TGF beta signaling in ERG-rearranged tumors. Further, 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 PCa 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.