CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
Menée à l'aide de modèles murins et d'échantillons biopsiques prélevés sur 44 patients atteints d'un adénocarcinome du pancréas, cette étude met en évidence un mécanisme par lequel la nucléotidase CD73, en activant l'axe Rhoa-ROCK-myosine II, favorise l'invasion des cellules cancéreuses par migration amiboïde ainsi que l'immunosuppression
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. CD73 controls Myosin II driven amoeboid invasion and immunosuppression in pancreatic cancer.
Science Advances 2023