The article details research into the initiation mechanism of ERG-driven prostate cancer (PCa), a highly prevalent form in Western populations. Using a combination of lineage tracing and single-cell analysis in mouse models and human samples, the study identifies that PCa initiates in a rare subset of basal cells called BasalLum cells, which coexpress luminal genes. These BasalLum cells quickly transition into a highly proliferative, multi-lineage intermediate (IM) cell population that ultimately differentiates into invasive luminal adenocarcinomas. Mechanistically, the authors discover that this IM state, crucial for tumorigenicity, is characterized by an ERG-specific chromatin state and is highly dependent on the transcription factor STAT3 and the epigenetic regulators KMT2A/MLL1 and DOT1L, identifying potential therapeutic vulnerabilities. The presence of the IM signature in human PCa correlates with a worse prognosis, suggesting clinical relevance for these findings.
References:
- Feng W, Ladewig E, Lange M, et al. ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L[J]. Nature Genetics, 2025: 1-15.
