Department of Medical Oncology, First Hospital of China Medical University, Shenyang, China.
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Am J Physiol Gastrointest Liver Physiol. 2021 Mar 1;320(3):G380-G395. doi: 10.1152/ajpgi.00185.2020. Epub 2021 Jan 27.
Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and represents one of the deadliest forms of human cancers. Previous studies showed that activation of Yes-associated protein 1 (YAP1) plays a key role in malignant transformation in the pancreas. In this study, we found that YAP1 regulates the expression of epithelial cell transforming 2 (ECT2), a guanine nucleotide exchange factor for Rho-like GTPases. By immunohistochemistry analysis of human tissues, we show that ECT2 is highly expressed in primary PDAC and liver metastasis but not in normal pancreas. These correlations were also observed in a mouse model of PDAC, where pancreatic transformation is driven by mutants of and . Notably, nuclear ECT2 is upregulated in the transition from preneoplastic lesions to PDAC. High levels of YAP1 or ECT2 expression correlates with the poor overall survival rate of patients with PDAC. We further demonstrate that ECT2 is required for pancreatic cancer cell proliferation and migration in vitro. Finally, using a syngeneic orthotopic xenograft mouse model for pancreatic cancer, we found that ablation of ECT2 expression reduces pancreatic cancer growth and dissemination to the liver. These findings highlight the critical role of ECT2 in promoting pancreatic cancer growth and metastasis and provides insights into the development of novel methods for early detection and treatment. Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancers. In this study, we identified a novel signaling mechanism involved in PDAC progression and metastasis. Yes-associated protein 1 mediates the expression of epithelial cell transforming 2, which is elevated in PDAC and correlates with poor survival. Epithelial cell transforming 2 is required for PDAC growth and metastasis. This study provides insights into the development of novel methods for early detection and treatment of PDAC.
胰腺导管腺癌（PDAC）具有高度转移性，是人类癌症中最致命的形式之一。先前的研究表明，Yes 相关蛋白 1（YAP1）的激活在胰腺恶性转化中发挥关键作用。在这项研究中，我们发现 YAP1 调节上皮细胞转化 2（ECT2）的表达，ECT2 是 Rho 样 GTPases 的鸟嘌呤核苷酸交换因子。通过对人类组织的免疫组织化学分析，我们表明 ECT2 在原发性 PDAC 和肝转移中高度表达，但在正常胰腺中不表达。这些相关性在 PDAC 的小鼠模型中也观察到，其中由 和 突变驱动胰腺转化。值得注意的是，核 ECT2 在从癌前病变到 PDAC 的转变中上调。YAP1 或 ECT2 表达水平高与 PDAC 患者总体生存率差相关。我们进一步证明 ECT2 是胰腺癌细胞在体外增殖和迁移所必需的。最后，使用胰腺癌细胞的同源原位异种移植小鼠模型，我们发现 ECT2 表达的缺失可减少胰腺癌细胞的生长和向肝脏的扩散。这些发现强调了 ECT2 在促进胰腺癌细胞生长和转移中的关键作用，并为开发新的早期检测和治疗方法提供了思路。胰腺导管腺癌是人类癌症中最致命的形式之一。在这项研究中，我们确定了一种新的信号机制，涉及 PDAC 的进展和转移。Yes 相关蛋白 1 介导上皮细胞转化 2 的表达，上皮细胞转化 2 在 PDAC 中升高，并与生存率差相关。上皮细胞转化 2 是 PDAC 生长和转移所必需的。这项研究为开发新的早期检测和治疗 PDAC 的方法提供了思路。
