CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

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...

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Detalles Bibliográficos
Autores: Samain, Remi, Maiques Carlos, Oscar, Monger, Joanne, Lam, Hoyin, Candido, Juliana, George, Samantha L., Ferrari, Nicola, KohIhammer, Leonie, Lunetto, Sophia, Varela, Adrian, Orgaz, Jose L., Vilardell, Felip, Olsina Kissler, Jorge Juan, Matias-Guiu, Xavier, Sarker, Debashis, Biddle, Adrian, Balkwill, Frances, Eyles, Jim, Wilkinson, Robert W., Kocher, Hemant M., Calvo, Fernando, Wells, Claire, Sanz Moreno, Victoria
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/464526
Acceso en línea:https://doi.org/10.1126/sciadv.adi0244
https://hdl.handle.net/10459.1/464526
Access Level:acceso abierto
Descripción
Sumario: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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