“Dr. Jekyll and Mr. Hyde”: AT2 Cells in Lung Regeneration and Tumor Development

Abstract Alveolar type II (AT2) cells, the primary stem cell population in the distal lung epithelium, are known to be the most common cell of origin for lung adenocarcinoma (LUAD). A recent study published in Cell Stem Cell reveals that KRASG12D mutant AT2 cells hijack lung regeneration programs to initiate lung adenocarcinoma, resembling “Dr. Jekyll and Mr. Hyde” where their “Jekyll” side promotes tissue repair while their “Hyde” side drives tumorigenesis. Sustained NF-κB activation drives lineage infidelity, enabling these mutant cells to bypass normal differentiation, remodel the surrounding microenvironment, and ultimately promote tumorigenesis.