CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells.
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ICR Authors
Authors
Samain, R
Maiques, O
Monger, J
Lam, H
Candido, J
George, S
Ferrari, N
KohIhammer, L
Lunetto, S
Varela, A
Orgaz, JL
Vilardell, F
Olsina, JJ
Matias-Guiu, X
Sarker, D
Biddle, A
Balkwill, FR
Eyles, J
Wilkinson, RW
Kocher, HM
Calvo, F
Wells, CM
Sanz-Moreno, V
Maiques, O
Monger, J
Lam, H
Candido, J
George, S
Ferrari, N
KohIhammer, L
Lunetto, S
Varela, A
Orgaz, JL
Vilardell, F
Olsina, JJ
Matias-Guiu, X
Sarker, D
Biddle, A
Balkwill, FR
Eyles, J
Wilkinson, RW
Kocher, HM
Calvo, F
Wells, CM
Sanz-Moreno, V
Document Type
Journal Article
Date
2023-10-20
Date Accepted
2023-09-06
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.
Citation
Science Advances, 2023, 9 (42), pp. eadi0244 -
Source Title
Science Advances
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
ISSN
2375-2548
eISSN
2375-2548
2375-2548
2375-2548