Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
Department of Electrical and Computer Engineering, Rice University, Houston, TX 77030, USA.
Cell Rep. 2021 Apr 13;35(2):108990. doi: 10.1016/j.celrep.2021.108990.
Pancreatic ductal adenocarcinoma (PDAC) is therapeutically recalcitrant and metastatic. Partial epithelial to mesenchymal transition (EMT) is associated with metastasis; however, a causal connection needs further unraveling. Here, we use single-cell RNA sequencing and genetic mouse models to identify the functional roles of partial EMT and epithelial stabilization in PDAC growth and metastasis. A global EMT expression signature identifies ∼50 cancer cell clusters spanning the epithelial-mesenchymal continuum in both human and murine PDACs. The combined genetic suppression of Snail and Twist results in PDAC epithelial stabilization and increased liver metastasis. Genetic deletion of Zeb1 in PDAC cells also leads to liver metastasis associated with cancer cell epithelial stabilization. We demonstrate that epithelial stabilization leads to the enhanced collective migration of cancer cells and modulation of the immune microenvironment, which likely contribute to efficient liver colonization. Our study provides insights into the diverse mechanisms of metastasis in pancreatic cancer and potential therapeutic targets.
胰腺导管腺癌 (PDAC) 治疗上具有抗性且易转移。部分上皮到间充质转化 (EMT) 与转移有关；然而，还需要进一步阐明因果关系。在这里，我们使用单细胞 RNA 测序和遗传小鼠模型来确定 PDAC 生长和转移中部分 EMT 和上皮稳定的功能作用。全局 EMT 表达特征鉴定了在人和鼠 PDAC 中跨越上皮-间充质连续体的约 50 个癌细胞簇。Snail 和 Twist 的联合遗传抑制导致 PDAC 上皮稳定和肝转移增加。PDAC 细胞中 Zeb1 的基因缺失也会导致与癌细胞上皮稳定相关的肝转移。我们证明上皮稳定导致癌细胞的集体迁移增强和免疫微环境的调节，这可能有助于有效地肝定植。我们的研究为胰腺癌转移的多种机制和潜在的治疗靶点提供了深入了解。
