Premium
Tumor‐associated macrophages (TAMs) depend on ZEB1 for their cancer‐promoting roles
Author(s) -
Cortés Marlies,
SanchezMoral Lidia,
de Barrios Oriol,
FernándezAceñero María J,
MartínezCampanario MC,
EsteveCodina Anna,
Darling Douglas S,
Győrffy Balázs,
Lawrence Toby,
Dean Douglas C,
Postigo Antonio
Publication year - 2017
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797345
Subject(s) - cancer research , tumor microenvironment , ccl2 , ccr2 , ovarian cancer , tumor progression , mesenchymal stem cell , cd74 , tumor associated macrophage , phenotype , epithelial–mesenchymal transition , cancer , metastasis , biology , inflammation , chemokine , medicine , immunology , cd8 , immune system , tumor cells , microbiology and biotechnology , chemokine receptor , gene , biochemistry , mhc class i
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.