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<p>Non-small cell lung cancer (NSCLC), the predominant subtype of lung cancer, remains a major global health challenge due to its complex etiology and resistance to therapy. Aberrant signaling through receptor tyrosine kinases (RTKs) and mitogen-activated protein kinases (MAPKs) drives tumor progression and immune modulation, underscoring the need for systems-level investigation. In this study, we employed mathematical modeling and experimental validation to dissect the dynamic interplay of EGFR, FGFR, and TNFR signaling in NSCLC cells and macrophages. Our flux-based sensitivity analysis revealed persistent pathway biases, highlighting DUSP1, DUSP4, and SPRY2 as critical high-flux regulators within the MAPK and PI3K/AKT cascades. Crosstalk analysis demonstrated that these proteins form an interconnected signaling axis influencing cytokine production (IL6, IL10, IL12, and TNF-α) and macrophage-mediated responses in the tumor microenvironment. Functional assays confirmed that silencing SPRY2 suppressed DUSP1 and DUSP4 expression, impaired cell migration, and induced G2/M arrest, establishing a coordinated regulatory network essential for NSCLC progression. Together, our findings integrate computational modeling with molecular validation to identify DUSP1, DUSP4, and SPRY2 as pivotal drivers of oncogenic signaling and immune regulation. These proteins represent promising therapeutic targets whose inhibition may disrupt tumor-promoting feedback loops and attenuate NSCLC growth and survival.</p>

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Emergence of Sprouty role from the signaling interplay of DUSP1 and DUSP4 interactions in NSCLC pathogenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月15日

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  • Manasi Tukrul,
  • Pooja Gulhane,
  • Shailza Singh

摘要

Non-small cell lung cancer (NSCLC), the predominant subtype of lung cancer, remains a major global health challenge due to its complex etiology and resistance to therapy. Aberrant signaling through receptor tyrosine kinases (RTKs) and mitogen-activated protein kinases (MAPKs) drives tumor progression and immune modulation, underscoring the need for systems-level investigation. In this study, we employed mathematical modeling and experimental validation to dissect the dynamic interplay of EGFR, FGFR, and TNFR signaling in NSCLC cells and macrophages. Our flux-based sensitivity analysis revealed persistent pathway biases, highlighting DUSP1, DUSP4, and SPRY2 as critical high-flux regulators within the MAPK and PI3K/AKT cascades. Crosstalk analysis demonstrated that these proteins form an interconnected signaling axis influencing cytokine production (IL6, IL10, IL12, and TNF-α) and macrophage-mediated responses in the tumor microenvironment. Functional assays confirmed that silencing SPRY2 suppressed DUSP1 and DUSP4 expression, impaired cell migration, and induced G2/M arrest, establishing a coordinated regulatory network essential for NSCLC progression. Together, our findings integrate computational modeling with molecular validation to identify DUSP1, DUSP4, and SPRY2 as pivotal drivers of oncogenic signaling and immune regulation. These proteins represent promising therapeutic targets whose inhibition may disrupt tumor-promoting feedback loops and attenuate NSCLC growth and survival.