Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets

Luca Cassetta; Stamatina Fragkogianni; Andrew H Sims; Agnieszka Swierczak; Lesley M Forrester; Hui Zhang; Daniel Y H Soong; Tiziana Cotechini; Pavana Anur; Elaine Y Lin; Antonella Fidanza; Martha Lopez-Yrigoyen; Michael R Millar; Alexandra Urman; Zhichao Ai; Paul T Spellman; E Shelley Hwang; J Michael Dixon; Lisa Wiechmann; Lisa M Coussens; Harriet O Smith; Jeffrey W Pollard

doi:10.1016/j.ccell.2019.02.009

Human Tumor-Associated Macrophage and Monocyte Transcriptional Landscapes Reveal Cancer-Specific Reprogramming, Biomarkers, and Therapeutic Targets

Cancer Cell. 2019 Apr 15;35(4):588-602.e10. doi: 10.1016/j.ccell.2019.02.009. Epub 2019 Mar 28.

Authors

Luca Cassetta¹, Stamatina Fragkogianni¹, Andrew H Sims², Agnieszka Swierczak¹, Lesley M Forrester³, Hui Zhang⁴, Daniel Y H Soong¹, Tiziana Cotechini⁵, Pavana Anur⁶, Elaine Y Lin⁵, Antonella Fidanza³, Martha Lopez-Yrigoyen³, Michael R Millar⁷, Alexandra Urman⁸, Zhichao Ai¹, Paul T Spellman⁶, E Shelley Hwang⁹, J Michael Dixon¹⁰, Lisa Wiechmann⁸, Lisa M Coussens⁵, Harriet O Smith¹¹, Jeffrey W Pollard¹²

Affiliations

¹ MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK.
² Applied Bioinformatics of Cancer, University of Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XR, UK.
³ MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
⁴ Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York 10461, USA.
⁵ Department of Cell, Developmental & Cancer Biology, and Knight Cancer Institute, Oregon Health & Science University, Portland 97239, USA.
⁶ Department of Molecular and Medical Genetics and Knight Cancer Institute, Oregon Health & Science University, Portland 97239, USA.
⁷ MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK; Aquila Biomedical, Edinburgh Bioquarter, Little France Road, Edinburgh EH16 4TJ, UK.
⁸ Department of Surgery, Montefiore Medical College, New York 10467, USA.
⁹ Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
¹⁰ Edinburgh Breast Unit and Breast Cancer Now Research Unit, University of Edinburgh, Edinburgh EH4 2XU, UK.
¹¹ Department of Obstetrics and Gynecology, Albert Einstein College of Medicine and Montefiore Medical Center, New York 10461, USA.
¹² MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York 10461, USA. Electronic address: jeff.pollard@ed.ac.uk.

Abstract

The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes.

Keywords: CCL8; SIGLEC1; breast cancer; endometrial cancer; human circulating monocytes; human macrophages; tumor microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antineoplastic Agents / pharmacology
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cellular Reprogramming*
Chemokine CCL8 / genetics
Chemokine CCL8 / metabolism
Endometrial Neoplasms / genetics
Endometrial Neoplasms / metabolism
Endometrial Neoplasms / pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Induced Pluripotent Stem Cells / metabolism
Macrophage Colony-Stimulating Factor / genetics
Macrophages / metabolism*
Macrophages / pathology
Molecular Targeted Therapy
Monocytes / metabolism*
Monocytes / pathology
Paracrine Communication*
Sialic Acid Binding Ig-like Lectin 1 / genetics
Sialic Acid Binding Ig-like Lectin 1 / metabolism
Signal Transduction
THP-1 Cells
Transcription, Genetic*
Tumor Microenvironment

Substances

Antineoplastic Agents
Biomarkers, Tumor
CCL8 protein, human
CSF1 protein, human
Chemokine CCL8
SIGLEC1 protein, human
Sialic Acid Binding Ig-like Lectin 1
Macrophage Colony-Stimulating Factor

Abstract

Publication types

MeSH terms

Substances

Grants and funding