Innate immunity controls prostate stem cell plasticity

NF-κB-driven basal cell reprogramming during prostate tumor initiation

The associated publication was selected as a cover manuscript for the September 2025 issue of Nature Cancer.

This project investigates how oncogenic Pten deletion reactivates plasticity in prostate basal stem cells and promotes tumor initiation in a region-specific manner.

Using lineage tracing, single-cell RNA-seq, ATAC-seq, organoid assays, and in vivo functional perturbation, we showed that prostate basal cells undergo stepwise reprogramming through hillock-like and hybrid basal–luminal states before acquiring proximal luminal features. This reprogramming occurs predominantly in the anterior and dorsolateral prostate and is associated with more aggressive tumor initiation.

A central finding of this study is that basal cell plasticity is controlled by activation of innate immune signaling, particularly the IL-1, JAK–STAT, and NF-κB pathways. Pharmacological inhibition of these pathways, as well as genetic deletion of Rela/p65, reduced basal-to-luminal reprogramming, myeloid cell recruitment, and early tumorigenesis.

These findings reveal a direct link between epithelial cell-of-origin, regional tissue identity, inflammatory signaling, and prostate cancer initiation.

Innate immunity and NF-κB signaling drive prostate basal stem cell plasticity, lineage reprogramming, and tumor initiation.

Publication

Jiang C*, Song Y*, et al.
Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation.
Nature Cancer (2025).
Read the paper

Highlights

  • Basal cells, but not luminal cells, show strong oncogene-induced plasticity after Pten deletion.
  • Reprogramming follows region-specific trajectories in the prostate.
  • Basal cells transition through hillock-like and hybrid basal–luminal states.
  • Innate immune pathways, including IL-1, JAK–STAT, and NF-κB, promote cell plasticity.
  • Inhibition of these pathways blocks reprogramming and reduces early tumor initiation.
  • Reprogramming signatures are also observed in human prostate cancer datasets.

My contribution

I contributed to the computational analysis of chromatin lanscatpe, bulk and single-cell transcriptomic datasets, including the characterization of epithelial cell states, reprogramming trajectories and regulatory programs associated with prostate tumor initiation.