CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells-Reference-Cited by-同舟云学术

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

Published:2023-10-20 Issue:42 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Samain Remi¹^ORCID,Maiques Oscar¹^ORCID,Monger Joanne¹,Lam Hoyin²³,Candido Juliana¹⁴,George Samantha¹^ORCID,Ferrari Nicola⁵⁶^ORCID,KohIhammer Leonie¹,Lunetto Sophia⁷,Varela Adrian¹,Orgaz Jose L.¹⁸^ORCID,Vilardell Felip⁹^ORCID,Olsina Jorge Juan¹⁰^ORCID,Matias-Guiu Xavier⁹¹¹^ORCID,Sarker Debashis²^ORCID,Biddle Adrian⁷^ORCID,Balkwill Frances R.¹^ORCID,Eyles Jim⁴^ORCID,Wilkinson Robert W.⁴^ORCID,Kocher Hemant M.¹²¹³^ORCID,Calvo Fernando⁵¹⁴,Wells Claire M.²^ORCID,Sanz-Moreno Victoria¹^ORCID

Affiliation:

1. Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

2. School of Cancer and Pharmaceutical Sciences, Kings College London, London SE1 1UL, UK.

3. GSK, R&D Portfolio, Strategy and Business Insights, GSK House, 980 Great West Road, Brentford, TW8 9GS, UK.

4. Oncology R&D, AstraZeneca, Cambridge CB21 6GH, UK.

5. Tumour Microenvironment Team, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

6. Translational Science and Experimental Medicine, Early Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

7. Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK.

8. Instituto de Investigaciones Biomédicas Sols-Morreale CSIC-UAM, 28029 Madrid, Spain.

9. Department of Pathology, University Hospital Arnau de Vilanova, University of Lleida, Lleida, Spain.

10. Department of Surgery, University Hospital Arnau de Vilanova, University of Lleida, Lleida, Spain.

11. IRBLLEIDA, IDIBELL, University Hospita of Bellvitge, CIBERONC, Lleida, Spain.

12. Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

13. Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, London, UK.

14. Instituto de Biomedicina y Biotecnologia de Cantabria, c/ Albert Einstein 22, E39011 Santander, Spain.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adi0244

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