Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
School of Cancer and Pharmaceutical Sciences, Kings College London, London SE1 1UL, UK.
Sci Adv. 2023 Oct 20;9(42):eadi0244. doi: 10.1126/sciadv.adi0244. Epub 2023 Oct 18.
Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK-Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA-ROCK-Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73-ROCK-Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.
胰腺导管腺癌（PDAC）由于其高转移倾向和免疫抑制微环境，预后非常差。本研究使用一系列胰腺癌细胞系、三维（3D）侵袭系统、基因芯片签名、微流控装置、小鼠模型和活体成像，证明了 PDAC 细胞中的 ROCK-Myosin II 活性支持转录程序，赋予阿米巴样侵袭和免疫抑制特征以及体内转移能力。此外，我们发现免疫检查点 CD73 在阿米巴样 PDAC 细胞中高度表达，并驱动其侵袭性、转移性和免疫调节特征。在机制上，CD73 在 PI3K 下游激活 RhoA-ROCK-Myosin II。人 PDAC 活检的组织微阵列结合生物信息学分析表明，具有高 CD73-ROCK-Myosin II 活性的圆形阿米巴样侵袭细胞及其免疫抑制微环境预示着患者预后不良。我们提出靶向阿米巴样 PDAC 细胞作为一种治疗策略。
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