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EMBO J. 2017 Nov 15;36(22):3336-3355. doi: 10.15252/embj.201797345. Epub 2017 Oct 16.

Tumor-associated macrophages (TAMs) depend on ZEB1 for their cancer-promoting roles.

Author information

1
Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
2
Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain.
3
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science & Technology, and Universitat Pompeu Fabra, Barcelona, Spain.
4
Department of Oral Immunology, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, USA.
5
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, and Semmelweis University 2 Department of Pediatrics, Budapest, Hungary.
6
Centre d'Immunologie de Marseille-Luminy, INSERM U1104 and CNRS MR7280, Marseille, France.
7
Department of Ophthalmology and Visual Sciences and Birth Defects Center, University of Louisville, Louisville, KY, USA.
8
Molecular Targets Program, James G. Brown Cancer Center, Louisville, KY, USA.
9
Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain idib412@clinic.cat.
10
ICREA, Barcelona, Spain.

Abstract

Accumulation of tumor-associated macrophages (TAMs) associates with malignant progression in cancer. However, the mechanisms that drive the pro-tumor functions of TAMs are not fully understood. ZEB1 is best known for driving an epithelial-to-mesenchymal transition (EMT) in cancer cells to promote tumor progression. However, a role for ZEB1 in macrophages and TAMs has not been studied. Here we describe that TAMs require ZEB1 for their tumor-promoting and chemotherapy resistance functions in a mouse model of ovarian cancer. Only TAMs that expressed full levels of Zeb1 accelerated tumor growth. Mechanistically, ZEB1 expression in TAMs induced their polarization toward an F4/80low pro-tumor phenotype, including direct activation of Ccr2 In turn, expression of ZEB1 by TAMs induced Ccl2, Cd74, and a mesenchymal/stem-like phenotype in cancer cells. In human ovarian carcinomas, TAM infiltration and CCR2 expression correlated with ZEB1 in tumor cells, where along with CCL2 and CD74 determined poorer prognosis. Importantly, ZEB1 in TAMs was a factor of poorer survival in human ovarian carcinomas. These data establish ZEB1 as a key factor in the tumor microenvironment and for maintaining TAMs' tumor-promoting functions.

KEYWORDS:

EMT; TAMs; ZEB1; macrophages; tumor microenvironment

PMID:
29038174
PMCID:
PMC5686549
[Available on 2018-11-15]
DOI:
10.15252/embj.201797345
[Indexed for MEDLINE]

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