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. Kocher; Fernando Calvo; Claire M. Wells; Victoria Sanz-Moreno

doi:10.1126/SCIADV.ADI0244

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 journal › Article › peer-review

6 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 language	English
Article number	adi0244
Journal	Science Advances
Volume	9
Issue number	42
DOIs	https://doi.org/10.1126/SCIADV.ADI0244
Publication status	Published - 2023

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Samain, R., Maiques, O., Monger, J., Lam, H., Candido, J., George, S., Ferrari, N., Kohihammer, L., Lunetto, S., Varela, A., Orgaz, J. L., Vilardell, F., Olsina, J. J., Matias-Guiu, X., Sarker, D., Biddle, A., Balkwill, F. R., Eyles, J., Wilkinson, R. W., ... Sanz-Moreno, V. (2023). CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells. Science Advances, 9(42), Article adi0244. https://doi.org/10.1126/SCIADV.ADI0244

@article{c69ab82309cf4f0a85aff3d881db4088,

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

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.",

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

note = "Funding Information: We thank H. Schmidt and C. Pegrum (Barts Preclinical Imaging Facilities) for help with animal experiments. We thank C. Thompson and C. Bevan (QM+Emulate Organs-on-Chips Centre) for help with liver metastasis-on-chip experiments. The work was supported by Barts Charity MGU0418 (R.S., O.M., J.M., S.G., and V.S.-M.), Organ-on-a-Chip Network and Emulate Proof of Concept Awards (R.S. and V.S.-M.), Cancer Research UK (CRUK) C33043/A24478 (O.M., L.K., and V.S.-M.), Pancreatic Cancer Research UK Fund (C.M.W.), National Centre for the 3Rs (S.L. and A.B.), The National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust and King{\textquoteright}s College London and/or the NIHR Clinical Research Facility (H.L.), and Grant Atracci{\'o}n de Talento Investigador 2019-T1/BMD-13642 funded by Comunidad de Madrid (J.L.O.). Publisher Copyright: {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

doi = "10.1126/SCIADV.ADI0244",

language = "English",

volume = "9",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "42",

}

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 2023, 'CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells', Science Advances, vol. 9, no. 42, adi0244. https://doi.org/10.1126/SCIADV.ADI0244

TY - JOUR

T1 - CD73 controls Myosin II–driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells

AU - Samain, Remi

AU - Maiques, Oscar

AU - Monger, Joanne

AU - Lam, Hoyin

AU - Candido, Juliana

AU - George, Samantha

AU - Ferrari, Nicola

AU - Kohihammer, Leonie

AU - Lunetto, Sophia

AU - Varela, Adrian

AU - Orgaz, Jose L.

AU - Vilardell, Felip

AU - Olsina, Jorge Juan

AU - Matias-Guiu, Xavier

AU - Sarker, Debashis

AU - Biddle, Adrian

AU - Balkwill, Frances R.

AU - Eyles, Jim

AU - Wilkinson, Robert W.

AU - Kocher, Hemant M.

AU - Calvo, Fernando

AU - Wells, Claire M.

AU - Sanz-Moreno, Victoria

N1 - Funding Information: We thank H. Schmidt and C. Pegrum (Barts Preclinical Imaging Facilities) for help with animal experiments. We thank C. Thompson and C. Bevan (QM+Emulate Organs-on-Chips Centre) for help with liver metastasis-on-chip experiments. The work was supported by Barts Charity MGU0418 (R.S., O.M., J.M., S.G., and V.S.-M.), Organ-on-a-Chip Network and Emulate Proof of Concept Awards (R.S. and V.S.-M.), Cancer Research UK (CRUK) C33043/A24478 (O.M., L.K., and V.S.-M.), Pancreatic Cancer Research UK Fund (C.M.W.), National Centre for the 3Rs (S.L. and A.B.), The National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility (H.L.), and Grant Atracción de Talento Investigador 2019-T1/BMD-13642 funded by Comunidad de Madrid (J.L.O.). Publisher Copyright: © 2023 The Authors, some rights reserved.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85174748321&partnerID=8YFLogxK

U2 - 10.1126/SCIADV.ADI0244

DO - 10.1126/SCIADV.ADI0244

M3 - Article

C2 - 37851808

AN - SCOPUS:85174748321

SN - 2375-2548

VL - 9

JO - Science Advances

JF - Science Advances

IS - 42

M1 - adi0244

ER -

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

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