N-WASP deficiency enhances oncogenic KRAS-mediated lung adenocarcinoma progression in mice
- 1School of Biological Sciences, Nanyang Technological University
Abstract
Objective: Oncogenic KRAS mutations drive 25-30% of western lung adenocarcinoma (LUAD) cases, however the mechanisms that restrain tumor progression remain poorly defined. N-Wiskott–Aldrich syndrome protein (N-WASP) regulates actin cytoskeleton dynamics and epithelial architecture, but its role in KRAS-driven lung tumorigenesis is unclear.
Methods: We generated a conditional N-WASP knockout in KRAS G12D -driven lung adenocarcinoma mice (N-WASP LKO /KRAS G12D ) using Sftpc-CreERT2, and assessed N-WASP knockdown A549 cells (A549 KD ) 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-WASP LKO ) markedly increased tumor number and size in KRAS G12D 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. A kinase inhibitor screen identified Rho-associated protein kinase (ROCK) activity as a driver of this hyperproliferative phenotype, with ROCK inhibition normalizing proliferation in N-WASP-deficient cells, linking elevated Rho/ROCK signaling to the increased ERK1/2 activation observed upon N-WASP loss. 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.
Conclusion: These results establish N-WASP as a critical suppressor of KRAS-driven lung adenocarcinoma, linking cytoskeletal integrity to oncogenic signaling and transcriptional regulation. Our findings highlight the interplay between actin dynamics, epithelial architecture, and KRAS signaling, suggesting that targeting N-WASP dependent pathways could modulate lung cancer aggressiveness and offer novel therapeutic opportunities.
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BibTeX
@article{verma2026nwasp,
title = {{N-WASP deficiency enhances oncogenic KRAS-mediated lung adenocarcinoma progression in mice}},
author = {Apoorva Verma and Nanyang Li and Pazhanichamy Kalailingam and Chaiyoung Kim and Ankur Sharma and Ying Hui Lee and Thirumaran Thanabalu},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1868586},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1868586/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - N-WASP deficiency enhances oncogenic KRAS-mediated lung adenocarcinoma progression in mice
AU - Apoorva Verma
AU - Nanyang Li
AU - Pazhanichamy Kalailingam
AU - Chaiyoung Kim
AU - Ankur Sharma
AU - Ying Hui Lee
AU - Thirumaran Thanabalu
PY - 2026
DA - 2026/10/08
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1868586
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1868586/full
AB - Objective: Oncogenic KRAS mutations drive 25-30% of western lung adenocarcinoma (LUAD) cases, however the mechanisms that restrain tumor progression remain poorly defined. N-Wiskott–Aldrich syndrome protein (N-WASP) regulates actin cytoskeleton dynamics and epithelial architecture, but its role in KRAS-driven lung tumorigenesis is unclear. Methods: We generated a conditional N-WASP knockout in KRAS G12D -driven lung adenocarcinoma mice (N-WASP LKO /KRAS G12D ) using Sftpc-CreERT2, and assessed N-WASP knockdown A549 cells (A549 KD ) 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-WASP LKO ) markedly increased tumor number and size in KRAS G12D 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. A kinase inhibitor screen identified Rho-associated protein kinase (ROCK) activity as a driver of this hyperproliferative phenotype, with ROCK inhibition normalizing proliferation in N-WASP-deficient cells, linking elevated Rho/ROCK signaling to the increased ERK1/2 activation observed upon N-WASP loss. 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. Conclusion: These results establish N-WASP as a critical suppressor of KRAS-driven lung adenocarcinoma, linking cytoskeletal integrity to oncogenic signaling and transcriptional regulation. Our findings highlight the interplay between actin dynamics, epithelial architecture, and KRAS signaling, suggesting that targeting N-WASP dependent pathways could modulate lung cancer aggressiveness and offer novel therapeutic opportunities.
SN - 2234-943X
ER -