J Clin Invest. 2014 Mar;124(3):1069-82. doi: 10.1172/JCI67280.
Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β₁ integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.
肿瘤抑制因子 TP53 的突变存在于许多人类癌症形式中，与肿瘤细胞侵袭和转移的增加有关。已经确定了几种促进具有 TP53 突变的癌细胞扩散的机制，包括增加整合素与质膜的靶向作用。在这里，我们证明了肌球蛋白-X（Myo10）在突变 p53 驱动的癌症侵袭中的作用。对来自 2 个乳腺癌数据集的基因表达谱进行分析表明，MYO10 在侵袭性癌症亚型中高表达。Myo10 在多种癌细胞系和癌症转移的小鼠模型中是乳腺癌细胞侵袭和扩散所必需的。对没有整合素结合域的 Myo10 突变体的评估表明，Myo10 将 β₁整合素运输到丝状伪足尖端的能力是侵袭所必需的。在癌细胞和小鼠胰腺导管腺癌中引入突变型 p53 可促进 Myo10 的表达，而抑制内源性突变型 p53 可降低 Myo10 水平和细胞侵袭。在临床乳腺癌中，Myo10 主要在侵袭边缘表达，与 TP53 突变的存在和预后不良相关。这些数据表明，Myo10 在突变 p53 驱动的癌症中的上调对于侵袭是必要的，并且质膜突起，如丝状伪足，可能作为专门的转移引擎。
