胰腺癌
转移
生物
癌症研究
罗亚
肿瘤微环境
肌球蛋白
癌细胞
免疫系统
癌症
病理
细胞生物学
免疫学
医学
信号转导
遗传学
作者
Rémi Samain,Óscar Maiques,Joanne Monger,Hoyin Lam,Juliana Candido,Samantha George,Nicola Ferrari,Leonie KohIhammer,Sophia Lunetto,Ana Varela,José L. Orgaz,Felip Vilardell,Jorge Juan Olsina Kissler,Xavier Matías‐Guiu,Debashis Sarker,Adrian Biddle,Frances R. Balkwill,Jim E. Eyles,Robert W. Wilkinson,Hemant M. Kocher,Fernando Calvo,Claire M. Wells,Victoria Sanz-Moreno
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2023-10-20
卷期号:9 (42)
标识
DOI:10.1126/sciadv.adi0244
摘要
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.
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