N-WASP deficiency enhances oncogenic KRAS-mediated lung adenocarcinoma progression in mice

We generated a conditional N-WASP knockout in KRASG12D-driven lung adenocarcinoma mice (N-WASPLKO/KRASG12D) using Sftpc-CreERT2, and assessed N-WASP knockdown A549 cells (A549KD) in 3D culture for tumor burden, ERK signaling, transcriptomic changes, and E-cadherin expression.Results: Conditional deletion of N-WASP in type II alveolar cells (N-WASPLKO) markedly increased tumor number and size in KRASG12D mice. The tumors isolated from these mice retained strong pro–surfactant protein C expression, confirming alveolar epithelial origin and predominantly adopted a solid growth pattern, indicative of disrupted epithelial organization.

Mechanistically, N-WASP loss enhanced KRAS-driven ERK1/2 activation in lung tissue, consistent with increased mitogenic signaling. In A549 cells, N-WASP deficiency disrupted cytoskeletal architecture, promoted proliferation, and impaired cell–cell adhesion, recapitulating in vivo tumor phenotypes. Transcriptomic profiling of N-WASP–deficient lungs revealed coordinated upregulation of genes regulating proliferation, cytoskeletal remodeling, and tumor-promoting pathways, alongside downregulation of epithelial differentiation and adhesion programs.