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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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Autores principales: Samain, Remi, Maiques, Oscar, Monger, Joanne, Lam, Hoyin, Candido, Juliana, George, Samantha, Ferrari, Nicola, KohIhammer, Leonie, Lunetto, Sophia, Varela, Adrian, Orgaz, Jose L., Vilardell, Felip, Olsina, Jorge Juan, Matias-Guiu, Xavier, Sarker, Debashis, Biddle, Adrian, Balkwill, Frances R., Eyles, Jim, Wilkinson, Robert W., Kocher, Hemant M., Calvo, Fernando, Wells, Claire M., Sanz-Moreno, Victoria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584351/
https://www.ncbi.nlm.nih.gov/pubmed/37851808
http://dx.doi.org/10.1126/sciadv.adi0244
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author Samain, Remi
Maiques, Oscar
Monger, Joanne
Lam, Hoyin
Candido, Juliana
George, Samantha
Ferrari, Nicola
KohIhammer, Leonie
Lunetto, Sophia
Varela, Adrian
Orgaz, Jose L.
Vilardell, Felip
Olsina, Jorge Juan
Matias-Guiu, Xavier
Sarker, Debashis
Biddle, Adrian
Balkwill, Frances R.
Eyles, Jim
Wilkinson, Robert W.
Kocher, Hemant M.
Calvo, Fernando
Wells, Claire M.
Sanz-Moreno, Victoria
author_facet Samain, Remi
Maiques, Oscar
Monger, Joanne
Lam, Hoyin
Candido, Juliana
George, Samantha
Ferrari, Nicola
KohIhammer, Leonie
Lunetto, Sophia
Varela, Adrian
Orgaz, Jose L.
Vilardell, Felip
Olsina, Jorge Juan
Matias-Guiu, Xavier
Sarker, Debashis
Biddle, Adrian
Balkwill, Frances R.
Eyles, Jim
Wilkinson, Robert W.
Kocher, Hemant M.
Calvo, Fernando
Wells, Claire M.
Sanz-Moreno, Victoria
author_sort Samain, Remi
collection PubMed
description 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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spelling pubmed-105843512023-10-19 CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells Samain, Remi Maiques, Oscar Monger, Joanne Lam, Hoyin Candido, Juliana George, Samantha Ferrari, Nicola KohIhammer, Leonie Lunetto, Sophia Varela, Adrian Orgaz, Jose L. Vilardell, Felip Olsina, Jorge Juan Matias-Guiu, Xavier Sarker, Debashis Biddle, Adrian Balkwill, Frances R. Eyles, Jim Wilkinson, Robert W. Kocher, Hemant M. Calvo, Fernando Wells, Claire M. Sanz-Moreno, Victoria Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2023-10-18 /pmc/articles/PMC10584351/ /pubmed/37851808 http://dx.doi.org/10.1126/sciadv.adi0244 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Samain, Remi
Maiques, Oscar
Monger, Joanne
Lam, Hoyin
Candido, Juliana
George, Samantha
Ferrari, Nicola
KohIhammer, Leonie
Lunetto, Sophia
Varela, Adrian
Orgaz, Jose L.
Vilardell, Felip
Olsina, Jorge Juan
Matias-Guiu, Xavier
Sarker, Debashis
Biddle, Adrian
Balkwill, Frances R.
Eyles, Jim
Wilkinson, Robert W.
Kocher, Hemant M.
Calvo, Fernando
Wells, Claire M.
Sanz-Moreno, Victoria
CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_full CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_fullStr CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_full_unstemmed CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_short CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
title_sort cd73 controls myosin ii–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584351/
https://www.ncbi.nlm.nih.gov/pubmed/37851808
http://dx.doi.org/10.1126/sciadv.adi0244
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