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

• Published in: The EMBO journal 2017-11, Vol.36 (22), p.3336-3355
• Main Authors: Cortés, Marlies, Sanchez‐Moral, Lidia, de Barrios, Oriol, Fernández‐Aceñero, María J, Martínez‐Campanario, MC, Esteve‐Codina, Anna, Darling, Douglas S, Győrffy, Balázs, Lawrence, Toby, Dean, Douglas C, Postigo, Antonio
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Differentiation, B-Lymphocyte - metabolism; Antitumor activity; Cancer; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - pathology; CCR2 protein; Cell activation; Cell Count; Cell Differentiation - drug effects; Chemokine CCL2 - pharmacology; Chemoresistance; Chemotherapy; Colony-Stimulating Factors - pharmacology; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm - drug effects; EMBO03; EMBO24; EMBO37; EMT; Female; Gelatinase B; Gene Expression Regulation, Neoplastic - drug effects; Genotype & phenotype; Histocompatibility Antigens Class II - metabolism; Humans; Infiltration; Macrophage Activation - drug effects; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Matrix Metalloproteinase 9 - metabolism; Medical prognosis; Mesenchyme; Metastases; Mice, Inbred C57BL; Models, Biological; Monocyte chemoattractant protein 1; Monocytes - drug effects; Monocytes - pathology; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Phenotype; Prognosis; Receptors, CCR2 - metabolism; Survival Analysis; TAMs; Tumor cells; tumor microenvironment; Tumors; Up-Regulation - drug effects; ZEB1; Zinc Finger E-box-Binding Homeobox 1 - metabolism
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201797345

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 F4/80 low 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. Synopsis Tumor‐associated macrophages (TAMs) require the expression of the EMT transcription factor ZEB1 for their cancer‐promoting functions. ZEB1 activates a F4/80 low phenotype in macrophages and inhibits their maturation into F4/80 high macrophages. ZEB1 is required for the activation of macrophages toward pro‐tumor F4/80 low TAMs. ZEB1 induces a Ccr2‐Mmp9‐Ccl2 positive loop between TAMs and cancer cells to enhance tumor progression. Expression of ZEB1 in TAMs and cancer cells correlates with poorer prognosis in human ovarian carcinomas. Graphical Abstract Tumor‐associated macrophages express the EMT‐associated transcription factor ZEB1, which drives their tumor‐promoting and chemotherapy‐resistance functions in mouse ovarian cancer models.