@article{10902/31060,
year = {2023},
url = {https://hdl.handle.net/10902/31060},
abstract = {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.},
organization = {Acknowledgments: We thank H. Schmidt and C. Pegrum (Barts Preclinical Imaging Facilities) for help with animal experiments. We thank C. Thompson and C. Bevan (QM+Emulate Organson-Chips Centre) for help with liver metastasis-on-chip experiments. 
Funding: The work was supported by Barts Charity MGU0418 (R.S., O.M., J.M., S.G., and V.S.-M.), Organ-on-a-Chip Network and Emulate Proof of Concept Awards (R.S. and V.S.-M.), Cancer Research UK (CRUK) C33043/A24478 (O.M., L.K., and V.S.-M.), Pancreatic Cancer Research UK Fund (C.M.W.), National Centre for the 3Rs (S.L. and A.B.), The National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility (H.L.), and Grant Atracción de Talento Investigador 2019-T1/BMD-13642 funded by Comunidad de Madrid (J.L.O.)},
publisher = {American Association for the Advancement of Science},
publisher = {Science Advances, 2023, 9, eadi0244},
title = {CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells},
author = {Samain, Remi and Maiques, Oscar and Monger, Joanne and Lam, Hoyin and Cándido, Juliana and George, Samantha and Ferrari, Nicola and Kohlhammer, Leonie and Lunetto, Sophia and Varela, Adrián and Orgaz, José L. and Vilardell, Felip and Olsina, Jorge Juan and Matias-Guiu, Xavier and Sarker, Debashis and Biddle, Adrian and Balkwill, Frances R. and Eyles, Jim and Calvo González, Fernando},
}