Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation

Area of Science:

• Prostate cancer research
• Stem cell biology
• Cancer epigenetics

Background:

• Prostate epithelium originates from multipotent stem cells, differentiating into lineage-restricted basal and luminal cells in adults.
• Loss of Pten in basal cells (BCs) can restore multipotency, but mechanisms of BC plasticity and tumor initiation remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms underlying basal cell plasticity and prostate tumor initiation following Pten deletion.
• To identify potential therapeutic targets for prostate cancer based on Pten-driven reprogramming.

Main Methods:

• Single-cell RNA sequencing and ATAC-seq were employed to analyze cell fate changes after Pten deletion.
• In situ characterization and pharmacological/genetic inhibition of key signaling pathways were performed.

Main Results:

• Pten deletion in prostate BCs induced regionalized cell fate reprogramming, characterized by a progression through hillock-like and proximal-like luminal states.
• This reprogramming was linked to the activation of innate immunity signaling pathways, including interleukin-1, JAK-STAT, and NF-κB.
• Inhibition of these pathways, either pharmacologically or genetically, effectively blocked Pten-induced BC plasticity and reprogramming.

Conclusions:

• Pten loss drives prostate basal cell plasticity and tumor initiation via a defined cell fate trajectory.
• Innate immunity pathways are critical mediators of Pten-driven prostate cancer development.
• Targeting IL-1, JAK-STAT, and NF-κB pathways presents a promising strategy for prostate cancer prevention and treatment.