腹腔转移是先进卵巢癌的一个主要特征，但促进卵巢癌转移和进展的关键蛋白质尚未定义。因此需要进行一项公正的高通量深入研究来揭示其机制。配对的原发性卵巢肿瘤和转移瘤的转录组测序揭示MAP4K4是一种高度表达的丝氨酸/苏氨酸激酶，属于Ste20激酶家族。在其他独立患者中进一步验证了转移中MAP4K4表达增加的情况。MAP4K4表达增加与较差的生存率、更高的CA125水平和更先进的FIGO阶段有关。 下调MAP4K4会抑制癌细胞的粘附、迁移和侵袭，并发现MAP4K4能稳定N-钙黏蛋白。更进一步的结果表明MAP4K4介导ADAM10在521位丝氨酸的磷酸化能够抑制ADAM10对N-钙黏蛋白的切割作用，从而导致N-钙黏蛋白稳定。通过药物抑制MAP4K4可以消除腹膜转移。总体来说，我们的研究揭示了MAP4K4是卵巢癌转移中的一个重要促进因素，而靶向MAP4K4可能是卵巢癌患者的潜在治疗方法。©2023.作者。

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.© 2023. The Author(s).