ERG-driven prostate cancer initiation is cell-context dependent and requires KMT2A and DOT1L.

Area of Science:

• Prostate cancer research
• Cancer cell biology
• Molecular oncology

Background:

• ERG transcription factor translocations are common in prostate cancer, but their tumorigenic mechanisms are unclear.
• Understanding ERG's role is crucial for developing targeted therapies.
• Identifying the specific cell types involved in ERG-driven prostate cancer is essential.

Purpose of the Study:

• To elucidate the mechanism of ERG-driven tumorigenicity in prostate cancer.
• To identify the specific cell populations responsible for initiating ERG-positive prostate tumors.
• To investigate the role of intermediate cells in ERG-driven prostate cancer progression.

Main Methods:

• Lineage tracing in murine models to track cell populations.
• Transcriptomic analysis of ERG-positive human prostate cancers.
• Single-cell analysis to identify cellular states and molecular features.
• In vivo tumorigenicity assays.

Main Results:

• Tumor-initiating ERG activity resides in rare Basal^Lum cells, not luminal cells.
• ERG activation induces Basal^Lum cells to form proliferative intermediate (IM) cells, which then transition to luminal cells.
• ERG⁺ IM cells in human prostate cancer correlate with a worse prognosis and exhibit specific chromatin states and gene expression patterns (STAT3, KMT2A/MLL1, DOT1L).

Conclusions:

• ERG drives prostate tumorigenesis through a specific lineage of basal cells that acquire luminal characteristics.
• Intermediate cells are key players in ERG-driven prostate cancer progression and are associated with poor outcomes.
• Targeting specific molecular pathways (STAT3, KMT2A/MLL1, DOT1L) in ERG⁺ IM cells presents potential therapeutic strategies.