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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.
Fuente: Science Advances, 2023, 9, eadi0244
Editorial: American Association for the Advancement of Science
Año de publicación: 2023
Nº de páginas: 20
Tipo de publicación: Artículo de Revista
DOI: 10.1126/sciadv.adi0244
ISSN: 2375-2548
Consultar en UCrea Leer publicación
SAMAIN, REMI
MAIQUES, OSCAR
MONGER, JOANNE
LAM, HOYIN
CÁNDIDO, JULIANA
GEORGE, SAMANTHA
FERRARI, NICOLA
KOHLHAMMER, LEONIE
LUNETTO, SOPHIA
VARELA, ADRIÁN
ORGAZ, JOSÉ L.
VILARDELL, FELIP
OLSINA, JORGE JUAN
MATIAS-GUIU, XAVIER
SARKER, DEBASHIS
BIDDLE, ADRIAN
BALKWILL, FRANCES R.
EYLES, JIM
FERNANDO CALVO GONZALEZ
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