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

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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

Original languageEnglish
Article number644
JournalCommunications Biology
Volume3
Issue number1
DOIs
Accepted/In press30 Sep 2020
Published1 Dec 2020

Bibliographical 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’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.

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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.

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