Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation
Frances J. England, Ignacio Bordeu, M. Ng, JaeHak Bang, Bumsoo Kim, Jinwook Choi, Erik Cardoso, Bon‐Kyoung Koo, Benjamin D. Simons, 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.