We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2–driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from β-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of β-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/β-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2–centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.

我们最近报道，通过 ADAM10 在 R87-T88 处的切割激活 Trop-2 是 Trop-2 驱动的结肠癌进展的基础。然而，Trop-2 在转移性扩散中的作用机制和病理影响仍未探索。通过寻找癌症转移的分子决定因素，我们发现TROP2在独立的结肠癌转移模型中具有独特的上调作用。KM12SM 人结肠癌细胞中野生型 Trop-2 的过表达增加了体内肝转移率在免疫抑制小鼠中。无尾、活化的 ΔcytoTrop-2 突变体进一步增强了转移性生长，表明 Trop-2 尾是一个关键的抑制信号元件。在原发性肿瘤和转移灶中，转录组分析显示CDH1没有下调通过上皮-间质转化的转录因子，因此表明 Trop-2 的前转移活性是通过替代机制。Trop-2 可以与 ADAM10 紧密交互。在这里，Trop-2 结合 E-cadherin 并刺激 ADAM10 介导的 E-cadherin 胞内结构域的蛋白水解切割。这会诱导 E-cadherin 从 β-actin 上脱离，细胞间粘附丧失，获得侵袭能力，以及 β-catenin 信号传导的膜驱动激活，而 ΔcytoTrop-2 突变体进一步增强了这些。这种 Trop-2/E-cadherin/β-catenin 程序导致抗凋亡信号传导、增加细胞迁移和增强癌细胞存活率。在结肠癌患者中，这种以 Trop-2 为中心的计划的激活导致无复发和总生存期显着降低，表明对转移性疾病进展的重大影响。最近，抗Trop-2 mAb Sacituzumab govitecan-hziy被证明对转移性乳腺癌具有活性。我们的研究结果定义了 Trop-2 作为转移性结肠癌靶点的关键相关性。