{
  "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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusion: 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.",
  "abstract_shown": true,
  "affiliations": [
    "School of Biological Sciences, Nanyang Technological University"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Apoorva Verma"
    },
    {
      "affs": [
        0
      ],
      "name": "Nanyang Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Pazhanichamy Kalailingam"
    },
    {
      "affs": [
        0
      ],
      "name": "Chaiyoung Kim"
    },
    {
      "affs": [
        0
      ],
      "name": "Ankur Sharma"
    },
    {
      "affs": [
        0
      ],
      "name": "Ying Hui Lee"
    },
    {
      "affs": [
        0
      ],
      "name": "Thirumaran Thanabalu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d4q208mns12d7.bib",
  "cited_by": 0,
  "doi": "10.3389/fonc.2026.1868586",
  "fulltext_url": "https://europepmc.org/articles/PMC13686841",
  "id": "d4q208mns12d7",
  "issns": [
    "2234-943X"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1868586/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Kinase Regulation and GTPase Signaling"
    ]
  ],
  "openalex": "W7220957101",
  "pdf_url": "https://europepmc.org/articles/PMC13686841?pdf=render",
  "pmcid": "PMC13686841",
  "pmid": "42923069",
  "published": "2026-10-08",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/d4q208mns12d7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:13Z",
      "native_id": "10.3389/fonc.2026.1868586",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1868586/full"
    },
    {
      "first_seen": "2026-10-30T12:20:36Z",
      "native_id": "MED:42923069",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42923069"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Kinase Regulation and GTPase Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "N-WASP deficiency enhances oncogenic KRAS-mediated lung adenocarcinoma progression in mice",
  "title_text": "N-WASP deficiency enhances oncogenic KRAS-mediated lung adenocarcinoma progression in mice",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:36Z",
  "url": "https://research.draconitic.com/paper/d4q208mns12d7",
  "venue": "Frontiers in Oncology",
  "versions": []
}