Peritoneal metastasis is a key feature of advanced ovarian cancer, but the critical protein required for ovarian cancer metastasis and progression is yet to be defined. Thus, an unbiased high throughput and in-depth study is warranted to unmask the mechanism. Transcriptomic sequencing of paired primary ovarian tumors and metastases unveiled that MAP4K4, a serine/threonine kinase belongs to the Ste20 family of kinases, was highly expressed in metastatic sites. Increased MAP4K4 expression in metastasis was further validated in other independent patients, with higher MAP4K4 expression associated with poorer survival, higher level of CA125 and more advanced FIGO stage. Down regulation of MAP4K4 inhibited cancer cell adhesion, migration, and invasion. Notably, MAP4K4 was found to stabilize N-cadherin. Further results showed that MAP4K4 mediated phosphorylation of ADAM10 at Ser436 results in suppression of N-cadherin cleavage by ADAM10, leading to N-cadherin stabilization. Pharmacologic inhibition of MAP4K4 abrogated peritoneal metastases. Overall, our data reveal MAP4K4 as a significant promoter in ovarian cancer metastasis. Targeting MAP4K4 may be a potential therapeutic approach for ovarian cancer patients.

腹膜转移是晚期卵巢癌的一个关键特征，但卵巢癌转移和进展所需的关键蛋白尚未明确。因此，有必要进行无偏见的高通量和深入研究以揭示该机制。配对的原发性卵巢肿瘤和转移瘤的转录组测序表明，MAP4K4 是一种丝氨酸/苏氨酸激酶，属于 Ste20 激酶家族，在转移部位高度表达。转移中增加的 MAP4K4 表达在其他独立患者中得到进一步验证，更高的 MAP4K4 表达与更差的生存、更高水平的 CA125 和更晚期的 FIGO 阶段相关。MAP4K4 的下调抑制了癌细胞的粘附、迁移和侵袭。值得注意的是，MAP4K4 被发现可以稳定 N-钙粘蛋白。进一步的结果表明，MAP4K4 介导的 ADAM10 在 Ser436 位点的磷酸化导致 ADAM10 对 N-钙粘蛋白的裂解的抑制，从而导致 N-钙粘蛋白稳定。MAP4K4 的药理学抑制消除了腹膜转移。总体而言，我们的数据显示 MAP4K4 是卵巢癌转移中的重要启动子。靶向 MAP4K4 可能是卵巢癌患者的一种潜在治疗方法。