对于颈淋巴结（cLN）或远处转移诊断出头颈癌（HNC）患者，生存率较低。HRAS癌基因组态变与HNC中的晚期肿瘤阶段和转移有关。阐明成功突变的HRAS（HRASmut）促进HNC转移的分子机制可能会为患者提供更好的治疗选择。在这里，我们使用HRASmut人类HNC细胞系、患者源性移植物（PDX）和一种新的HRASmut同基因模型，检查了HRAS突变引发的体外和体内转移。遗传和药理学操作表明，HRASmut足以驱动体内转移和体外入侵。定向蛋白质组学分析显示，HRASmut通过抑制Hippo通路和稳定YAP1活动来促进AXL表达。使用法尼西尔基转移酶抑制剂Tipifarnib阻断HRAS信号，激活Hippo通路并减少YAP1的核外转移，从而抑制YAP1介导的AXL表达和转移。AXL是HRASmut细胞体内迁移和体外入侵以及形成区域性cLN和肺转移所必需的。此外，去除AXL的HRASmut肿瘤在原发肿瘤中显示出淋巴和血管新生的减少。Tipifarnib治疗还降低了AXL表达并减弱了VEGFA和VEGFC表达，从而调节肿瘤诱导的血管形成和转移。我们的结果表明，YAP1和AXL是HRASmut引起的转移的关键因素，并且Tipifarnib治疗可以通过增强YAP1的细胞质封闭和下调AXL表达来限制HRAS突变的HNC肿瘤的转移。

The survival rate for head and neck cancer (HNC) patients diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts (PDXs), and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also reduced AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.