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

Remi Samain, Oscar Maiques, Joanne Monger, Hoyin Lam, Juliana Candido, Samantha George, Nicola Ferrari, Leonie Kohihammer, Sophia Lunetto, Adrian Varela, Jose L. Orgaz, Felip Vilardell, Jorge Juan Olsina, Xavier Matias-Guiu, Debashis Sarker, Adrian Biddle, Frances R. Balkwill, Jim Eyles, Robert W. Wilkinson, Hemant M. KocherFernando Calvo, Claire M. Wells, Victoria Sanz-Moreno*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metas-tasize 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.

Original languageEnglish
Article numberadi0244
JournalScience Advances
Volume9
Issue number42
DOIs
Publication statusPublished - 2023

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