Peng Hsuan-Yu, Chang Kwang-Yu, Chang Wei-Min, Wu Chia-Yu, Lee Hsin-Lun, Chang Yung-Chieh, Liu Ko-Jiunn, Shiah Shine-Gwo, Kuo Ching-Chuan, Chang Jang-Yang
TMU Research Center of Cancer Translational Medicine, Taipei Medical University Hospital, College of Medicine, Taipei Medical University, Taipei, 110301 Taiwan, ROC.
National Institute of Cancer Research, National Health Research Institutes, Tainan, 70456, Taiwan, ROC; Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Neoplasia. 2025 Aug;66:101193. doi: 10.1016/j.neo.2025.101193. Epub 2025 Jun 4.
Oral squamous cell carcinoma (OSCC) is an aggressive malignancy frequently characterized by dysregulated epidermal growth factor receptor (EGFR) signaling. Among EGFR mutation, EGFRvIII, an extracellular domain truncated form without exons 2-7, exhibits ligand-independent and constitutive EGFR activation. Although EGFRvIII functions as an oncogene in glioblastoma, its role in OSCC remains unclear. Here, we demonstrate that EGFRvIII is highly prevalent in OSCC, with approximately 70 % of OSCC tumor samples revealing high EGFRvIII expression. EGFRvIII enhances metastatic and proliferative potential, while its knockdown significantly reduces these malignant phenotypes. Beyond its direct oncogenic effects, EGFRvIII actively remodels the tumor microenvironment (TME) by recruiting and activating fibroblasts. In both xenograft models and co-culture systems, OSCC cells expressing EGFRvIII stimulated the expression of fibroblast activation markers-including α-smooth muscle actin (α-SMA), platelet-derived growth factor receptors (PDGFRA/PDGFRB), and collagen-thereby promoting a tumor-supportive stroma. Moreover, RNA sequencing and cytokine array analyses revealed that EGFRvIII induces lipocalin-2 (LCN2) expression and secretion. Elevated LCN2 in the conditioned medium from OSCC-EGFRvIII cells further stimulates fibroblast activation via the STAT3 signaling pathway, as pharmacological inhibition of STAT3 attenuates LCN2-driven fibroblast activation. Furthermore, exposure to environmental carcinogens such as nicotine-derived nitrosamine ketone (NNK) and arecoline enhances EGFRvIII expression and downstream signaling, exacerbating tumor aggressiveness. These findings reveal a positive feedback loop in which EGFRvIII fosters OSCC progression by stimulating LCN2-STAT3-mediated fibroblast activation. Targeting EGFRvIII and its downstream effectors may therefore represent a promising strategy to mitigate OSCC progression and improve therapeutic outcomes.
口腔鳞状细胞癌（OSCC）是一种侵袭性恶性肿瘤，其特征通常是表皮生长因子受体（EGFR）信号失调。在EGFR突变中，EGFRvIII是一种无外显子2 - 7的细胞外结构域截短形式，表现出不依赖配体的组成型EGFR激活。尽管EGFRvIII在胶质母细胞瘤中作为癌基因发挥作用，但其在OSCC中的作用仍不清楚。在此，我们证明EGFRvIII在OSCC中高度普遍，约70%的OSCC肿瘤样本显示EGFRvIII高表达。EGFRvIII增强转移和增殖潜能，而其敲低显著降低这些恶性表型。除了直接的致癌作用外，EGFRvIII通过招募和激活成纤维细胞积极重塑肿瘤微环境（TME）。在异种移植模型和共培养系统中，表达EGFRvIII的OSCC细胞刺激成纤维细胞激活标志物的表达，包括α - 平滑肌肌动蛋白（α - SMA）、血小板衍生生长因子受体（PDGFRA/PDGFRB）和胶原蛋白，从而促进肿瘤支持性基质的形成。此外，RNA测序和细胞因子阵列分析表明EGFRvIII诱导脂质运载蛋白2（LCN2）的表达和分泌。来自OSCC - EGFRvIII细胞的条件培养基中升高的LCN2通过STAT3信号通路进一步刺激成纤维细胞激活，因为STAT3的药理学抑制减弱了LCN2驱动的成纤维细胞激活。此外，暴露于尼古丁衍生的亚硝胺酮（NNK）和槟榔碱等环境致癌物会增强EGFRvIII的表达和下游信号传导，加剧肿瘤侵袭性。这些发现揭示了一个正反馈回路，其中EGFRvIII通过刺激LCN2 - STAT3介导的成纤维细胞激活促进OSCC进展。因此，靶向EGFRvIII及其下游效应器可能是减轻OSCC进展并改善治疗结果的一种有前景的策略。
