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Cell. 2019 Feb 7;176(4):757-774.e23. doi: 10.1016/j.cell.2018.12.038. Epub 2019 Jan 31.

Regional Activation of Myosin II in Cancer Cells Drives Tumor Progression via a Secretory Cross-Talk with the Immune Microenvironment.

Author information

1
Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK.
2
Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK; Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK.
3
Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK; Department of Imaging Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, St. Thomas Hospital, King's College London, London SE1 7EH, UK.
4
Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK; Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK; Tumour-Stroma Interactions in Cancer Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
5
St John's Institute of Dermatology, King's College London and National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London SE1 9RT, UK.
6
St John's Institute of Dermatology, King's College London and National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London SE1 9RT, UK; Department of Oncology, Haematology and Stem Cell Transplantation, University Hospital of Hamburg Eppendorf, Hamburg 20246, Germany.
7
St John's Institute of Dermatology, King's College London and National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Hospitals and King's College London, London SE1 9RT, UK; School of Cancer and Pharmaceutical Sciences, Guy's Hospital, King's College London, London SE1 9RT, UK.
8
Departments of Pathology Hospital U Arnau de Vilanova and Hospital U de Bellvitge, IRBLLEIDA, IDIBELL, University of Lleida, CIBERONC, Lleida, Spain.
9
Department of Dermatology, Hospital U Arnau de Vilanova, IRBLLEIDA, University of Lleida, CIBERONC, Lleida, Spain.
10
Tumour-Stroma Interactions in Cancer Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
11
Department of Imaging Chemistry and Biology, Division of Imaging Sciences and Biomedical Engineering, St. Thomas Hospital, King's College London, London SE1 7EH, UK.
12
Barts Cancer Institute, John Vane Science Building, Charterhouse Square, Queen Mary University of London, London EC1M 6BQ, UK; Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK. Electronic address: v.sanz-moreno@qmul.ac.uk.

Abstract

ROCK-Myosin II drives fast rounded-amoeboid migration in cancer cells during metastatic dissemination. Analysis of human melanoma biopsies revealed that amoeboid melanoma cells with high Myosin II activity are predominant in the invasive fronts of primary tumors in proximity to CD206+CD163+ tumor-associated macrophages and vessels. Proteomic analysis shows that ROCK-Myosin II activity in amoeboid cancer cells controls an immunomodulatory secretome, enabling the recruitment of monocytes and their differentiation into tumor-promoting macrophages. Both amoeboid cancer cells and their associated macrophages support an abnormal vasculature, which ultimately facilitates tumor progression. Mechanistically, amoeboid cancer cells perpetuate their behavior via ROCK-Myosin II-driven IL-1α secretion and NF-κB activation. Using an array of tumor models, we show that high Myosin II activity in tumor cells reprograms the innate immune microenvironment to support tumor growth. We describe an unexpected role for Myosin II dynamics in cancer cells controlling myeloid function via secreted factors.

KEYWORDS:

NF-κB; ROCK-Myosin II; macrophages; protein secretion; rounded-amoeboid melanoma cells; tumor invasive front

PMID:
30712866
PMCID:
PMC6370915
DOI:
10.1016/j.cell.2018.12.038
[Indexed for MEDLINE]
Free PMC Article

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