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

  • Nat Cancer. 2025 Sep;6(9):1537-1558. doi: 10.1038/s43018-025-00994-3.
Chen Jiang  #  1 ,  Yura Song  #  1 ,  Sandrine Rorive  2 ,  Justine Allard  3 ,  Elisavet Tika  1 ,  Zahra Zahedi  1 ,  Christine Dubois  1 ,  Isabelle Salmon  2 ,  Alejandro Sifrim  4 ,  Cédric Blanpain  5  6
Affiliations
  • 1. Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium.
  • 2. Centre Universitaire Inter Regional d'Expertise en Anatomie Pathologique Hospitalière, CurePath (CHIREC - CHU TIVOLI -Université Libre de Bruxelles), Charleroi, Belgium.
  • 3. DIAPath, Center for microscopy and molecular Imaging, Université Libre de Bruxelles, Gosselies, Belgium.
  • 4. Department of Human Genetics, University of Leuven, KU Leuven, Leuven, Belgium.
  • 5. Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium. [email protected].
  • 6. WEL Research Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium. [email protected].
  • # Contributed equally.
PMID: 40550901 DOI: 10.1038/s43018-025-00994-3
Abstract

Prostate epithelium develops from multipotent stem cells, which are replaced in adult life by different lineage-restricted basal and luminal unipotent stem cells. Deletion of PTEN re-induces multipotency in basal cells (BCs); however, the molecular mechanisms regulating BC plasticity and tumor initiation are poorly understood. Here we showed that PTEN deletion in BCs led to distinct cell fate reprogramming and tumor initiation in a regionalized manner. Single-cell RNA Sequencing, ATAC-seq and in situ characterization revealed that following PTEN deletion in anterior and dorsolateral prostates, BCs were highly plastic and reprogrammed into a hillock-like state, progressing into a proximal-like luminal state before giving rise to invasive tumors. This BC reprogramming was associated with the activation of innate immunity. Pharmacological targeting of interleukin-1, JAK-STAT and NF-κB as well as genetic deletion of Nfkb inhibit Pten-induced cell plasticity and reprogramming in a cellular autonomous manner, opening new opportunities for prevention and treatment of prostate Cancer.

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