Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype

Richard Beatson; Rosalind Graham; Fabio Grundland Freile; Domenico Cozzetto; Shichina Kannambath; Ester Pfeifer; Natalie Woodman; Julie Owen; Rosamond Nuamah; Ulla Mandel; Sarah Pinder; Cheryl Gillett; Thomas Noll; Ihssane Bouybayoune; Joyce Taylor-Papadimitriou; Joy M. Burchell

doi:10.1038/s42003-020-01359-5

Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype

Richard Beatson^*, Rosalind Graham, Fabio Grundland Freile, Domenico Cozzetto, Shichina Kannambath, Ester Pfeifer, Natalie Woodman, Julie Owen, Rosamond Nuamah, Ulla Mandel, Sarah Pinder, Cheryl Gillett, Thomas Noll, Ihssane Bouybayoune, Joyce Taylor-Papadimitriou, Joy M. Burchell

^*Corresponding author for this work

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Abstract

The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.

Original language	English
Article number	644
Journal	Communications Biology
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s42003-020-01359-5
Publication status	Published - 1 Dec 2020

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Beatson et al Commun Biolo AcceptedAccepted author manuscript, 18 MB

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Beatson, R., Graham, R., Grundland Freile, F., Cozzetto, D., Kannambath, S., Pfeifer, E., Woodman, N., Owen, J., Nuamah, R., Mandel, U., Pinder, S., Gillett, C., Noll, T., Bouybayoune, I., Taylor-Papadimitriou, J., & Burchell, J. M. (2020). Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype. Communications Biology, 3(1), Article 644. https://doi.org/10.1038/s42003-020-01359-5

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title = "Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype",

abstract = "The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.",

author = "Richard Beatson and Rosalind Graham and {Grundland Freile}, Fabio and Domenico Cozzetto and Shichina Kannambath and Ester Pfeifer and Natalie Woodman and Julie Owen and Rosamond Nuamah and Ulla Mandel and Sarah Pinder and Cheryl Gillett and Thomas Noll and Ihssane Bouybayoune and Joyce Taylor-Papadimitriou and Burchell, {Joy M.}",

note = "Funding Information: This work was supported by MRC grants MR/R000026/1 and MR/J007196/1 and CRUK KHP Centre Grant. We thank to Mansoor Saqi, Ulrich Kaldolsky and Rianne Wester of The National Institute for Health Research Biomedical Research Centre at Guy{\textquoteright}s and St. Thomas{\textquoteright} NHS Foundation Trust; The National Health Service Blood and Transplant Service, in particular Michael Saunders and Julie Stacey, for supplying leucocyte cones from healthy donors; Nicola O{\textquoteright}Reilly at the Peptide Synthesis Lab at the CRICK Institute for support and lyophilisation; Katie Flaherty for co-scoring images and Toby Lawrence for helpful discussion. The first author would like to dedicate this work to the memory of Lucy Beatson who passed away during the course of this work. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = dec,

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doi = "10.1038/s42003-020-01359-5",

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Beatson, R , Graham, R , Grundland Freile, F, Cozzetto, D, Kannambath, S, Pfeifer, E, Woodman, N, Owen, J, Nuamah, R, Mandel, U, Pinder, S , Gillett, C, Noll, T, Bouybayoune, I , Taylor-Papadimitriou, J & Burchell, JM 2020, 'Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype', Communications Biology, vol. 3, no. 1, 644. https://doi.org/10.1038/s42003-020-01359-5

TY - JOUR

T1 - Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype

AU - Beatson, Richard

AU - Graham, Rosalind

AU - Grundland Freile, Fabio

AU - Cozzetto, Domenico

AU - Kannambath, Shichina

AU - Pfeifer, Ester

AU - Woodman, Natalie

AU - Owen, Julie

AU - Nuamah, Rosamond

AU - Mandel, Ulla

AU - Pinder, Sarah

AU - Gillett, Cheryl

AU - Noll, Thomas

AU - Bouybayoune, Ihssane

AU - Taylor-Papadimitriou, Joyce

AU - Burchell, Joy M.

N1 - Funding Information: This work was supported by MRC grants MR/R000026/1 and MR/J007196/1 and CRUK KHP Centre Grant. We thank to Mansoor Saqi, Ulrich Kaldolsky and Rianne Wester of The National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ NHS Foundation Trust; The National Health Service Blood and Transplant Service, in particular Michael Saunders and Julie Stacey, for supplying leucocyte cones from healthy donors; Nicola O’Reilly at the Peptide Synthesis Lab at the CRICK Institute for support and lyophilisation; Katie Flaherty for co-scoring images and Toby Lawrence for helpful discussion. The first author would like to dedicate this work to the memory of Lucy Beatson who passed away during the course of this work. Publisher Copyright: © 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.

AB - The tumour microenvironment plays a crucial role in the growth and progression of cancer, and the presence of tumour-associated macrophages (TAMs) is associated with poor prognosis. Recent studies have demonstrated that TAMs display transcriptomic, phenotypic, functional and geographical diversity. Here we show that a sialylated tumour-associated glycoform of the mucin MUC1, MUC1-ST, through the engagement of Siglec-9 can specifically and independently induce the differentiation of monocytes into TAMs with a unique phenotype that to the best of our knowledge has not previously been described. These TAMs can recruit and prolong the lifespan of neutrophils, inhibit the function of T cells, degrade basement membrane allowing for invasion, are inefficient at phagocytosis, and can induce plasma clotting. This macrophage phenotype is enriched in the stroma at the edge of breast cancer nests and their presence is associated with poor prognosis in breast cancer patients.

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U2 - 10.1038/s42003-020-01359-5

DO - 10.1038/s42003-020-01359-5

M3 - Article

C2 - 33149188

AN - SCOPUS:85094975843

SN - 2399-3642

VL - 3

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 644

ER -

Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype

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