Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation Journal Article
| Authors: | England, F. J.; Bordeu, I.; Ng, M. E.; Bang, J.; Kim, B.; Choi, J.; Cardoso, E. C.; Koo, B. K.; Simons, B. D.; Lee, J. H. |
| Article Title: | Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation |
| 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. © 2025 The Author(s) |
| Keywords: | controlled study; nonhuman; animal cell; mouse; animal tissue; cell function; animal experiment; animal model; cohort analysis; lung cancer; immunoglobulin enhancer binding protein; in vivo study; cell differentiation; transcriptomics; wild type; cell lineage; stem cell; cell subpopulation; cell regeneration; oncogene k ras; cell clone; tumor growth; lung carcinogenesis; genetic conservation; cell mutant; nuclear reprogramming; single cell analysis; lung alveolus cell type 2; cell plasticity; interleukin 1 receptor type i; male; female; article; lineage tracing; tumor evolution; nf kb signaling; at2 clone dynamics; cell fate plasticity; clonal modeling; lung stem cells; nf-κb activation; regeneration program; stem cell competition; tumor ecosystem dynamics |
| Journal Title: | Cell Stem Cell |
| Volume: | 32 |
| Issue: | 3 |
| ISSN: | 1934-5909 |
| Publisher: | Cell Press |
| Date Published: | 2025-03-06 |
| Start Page: | 375 |
| End Page: | 390.e9 |
| Language: | English |
| DOI: | 10.1016/j.stem.2025.01.011 |
| PUBMED: | 39978341 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding author is Joo-Hyeon Lee -- Source: Scopus |
