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Memorial Sloan Kettering Cancer Center

Cell Stem Cell, Feb 13 2025, S1934-5909(25)00011-6 | https://doi.org/10.1016/j.stem.2025.01.011 Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation

Frances J. England ¹, Ignacio Bordeu ^{2 3}, Minn-E. Ng ¹, JaeHak Bang ¹, Bumsoo Kim ¹, Jinwook Choi ¹, Erik C. Cardoso ¹, Bon-Kyoung Koo ⁴, Benjamin D. Simons ^{1 2 5 *}, Joo-Hyeon Lee ^{1 6 7 *}

¹Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
²Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK
³Departamento de Física, Facultad de Ciencias Físicas y Matemáticas, Universidad de Chile, Santiago, Chile
⁴Center for Genome Engineering, Institute for Basic Science, Daejeon 34126, Republic of Korea
⁵Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Science, University of Cambridge, Cambridge CB3 0WA, UK
⁶Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

⁷Lead contact

^*Corresponding authors: correspondence to Benjamin D. Simons or Joo-Hyeon Lee

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.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-28)
연구진국내+국외 연구진
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