Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation

Cell Stem Cell. 2025 Mar 6;32(3):375-390.e9. doi: 10.1016/j.stem.2025.01.011. Epub 2025 Feb 19.

Abstract

Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.

Keywords: AT2 clone dynamics; NF-κB activation; cell fate plasticity; cell plasticity; clonal modeling; lineage tracing; lung cancer; lung stem cells; regeneration program; stem cell competition; tumor ecosystem dynamics; tumor evolution.

MeSH terms

  • Alveolar Epithelial Cells* / metabolism
  • Alveolar Epithelial Cells* / pathology
  • Animals
  • Carcinogenesis* / pathology
  • Cell Differentiation
  • Cell Transformation, Neoplastic* / pathology
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mutation* / genetics
  • NF-kappa B* / metabolism
  • Pulmonary Alveoli* / pathology
  • Regeneration*
  • Stem Cells* / metabolism
  • Stem Cells* / pathology

Substances

  • NF-kappa B