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

Marlies Cortés, Lidia Sanchez-Moral, Oriol de Barrios, María J. Fernández-Aceñero, M. C. Martínez-Campanario, Anna Esteve-Codina, Douglas S. Darling, B. Györffy, Toby Lawrence, Douglas C. Dean, Antonio Postigo

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3336-3355
Number of pages20
JournalEMBO Journal
Volume36
Issue number22
DOIs
Publication statusPublished - Nov 15 2017

Keywords

  • EMT
  • macrophages
  • TAMs
  • tumor microenvironment
  • ZEB1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Cortés, M., Sanchez-Moral, L., de Barrios, O., Fernández-Aceñero, M. J., Martínez-Campanario, M. C., Esteve-Codina, A., Darling, D. S., Györffy, B., Lawrence, T., Dean, D. C., & Postigo, A. (2017). Tumor-associated macrophages (TAMs) depend on ZEB1 for their cancer-promoting roles. EMBO Journal, 36(22), 3336-3355. https://doi.org/10.15252/embj.201797345