Understanding the molecular mechanisms regulating tumor dissemination and therapeutic resistance is of central importance for effective cancer therapies. Here, we report that nerve growth factor (NGF) and its receptor TrkA facilitate epithelial-mesenchymal transition (EMT) and EGFR inhibitor resistance via STAT3 activation in head and neck squamous cell carcinoma (HNSCC). Both NGF and TrkA expression were elevated in HNSCC, indicating poor clinical outcomes. NGF was highly expressed in cancer cells and nerves in perineural niche, whereas TrkA expression was higher in cancer cells with perineural invasion. The NGF/TrkA axis could promote HNSCC cell dissemination and trigger EMT via STAT3 activation. Moreover, we discovered that the NGF/TrkA axis conferred resistance to the EGFR inhibitor erlotinib via EMT processes in HNSCC cells. Blocking TrkA signaling markedly reversed EMT and sensitized HNSCC cells to erlotinib in both in vitro and in vivo models. Overall, our results demonstrate novel evidence that the paracrine NGF/TrkA axis favors EMT and confers EGFR-targeted therapeutic resistance in HNSCC.

中文翻译：

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头颈部鳞状细胞癌中的神经生长因子（NGF）-TrkA轴触发EMT并赋予对EGFR抑制剂厄洛替尼的耐药性。

理解调节肿瘤扩散和治疗抗性的分子机制对于有效的癌症治疗至关重要。在这里，我们报道神经生长因子（NGF）及其受体TrkA通过STAT3激活在头颈部鳞状细胞癌（HNSCC）中促进上皮-间质转化（EMT）和EGFR抑制剂抵抗。HNSCC中NGF和TrkA的表达均升高，表明临床预后较差。NGF在神经周围小生境的癌细胞和神经中高表达，而TrkA表达在神经周围浸润的癌细胞中高。NGF / TrkA轴可以促进HNSCC细胞的传播并通过STAT3激活触发EMT。此外，我们发现NGF / TrkA轴通过HNSCC细胞中的EMT过程赋予了对EGFR抑制剂埃洛替尼耐药性。在体外和体内模型中，阻断TrkA信号均显着逆转了EMT，并使HNSCC细胞对厄洛替尼敏感。总体而言，我们的结果表明新证据表明旁分泌NGF / TrkA轴在HNSCC中有利于EMT并赋予EGFR靶向治疗耐药性。