CD47 is a direct target of SNAI1 and ZEB1 and its blockade activates the phagocytosis of breast cancer cells undergoing EMT. (3rd April 2018)

• Record Type: Journal Article
• Authors: Noman, Muhammad Zaeem; Van Moer, Kris; Marani, Vanessa; Gemmill, Robert M.; Tranchevent, Léon-Charles; Azuaje, Francisco; Muller, Arnaud; Chouaib, Salem; Thiery, Jean Paul; Berchem, Guy; Janji, Bassam
• Is Part Of: Oncoimmunology. Volume 7:Number 4(2018)
• Publication Date: 2018-04-03
• Subjects: Breast cancer -- CD47 -- Dendritic cells -- Epithelial to Mesenchymal Transition -- Immune checkpoint -- Macrophage -- Phagocytosis and Immunotherapy -- ZEB1; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2017.1345415
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: We report that CD47 was upregulated in different EMT-activated human breast cancer cells versus epithelial MCF7 cells. Overexpression of SNAI1 or ZEB1 in epithelial MCF7 cells activated EMT and upregulated CD47 while siRNA-mediated targeting of SNAI1 or ZEB1 in mesenchymal MDA-MB-231 cells reversed EMT and strongly decreased CD47. Mechanistically, SNAI1 and ZEB1 upregulated CD47 by binding directly to E-boxes in the human CD47 promoter. TCGA and METABRIC data sets from breast cancer patients revealed that CD47 correlated with SNAI1 and Vimentin. At functional level, different EMT-activated breast cancer cells were less efficiently phagocytosed by macrophages vs. MCF7 cells. The phagocytosis of EMT-activated cells was rescued by using CD47 blocking antibody or by genetic targeting of SNAI1, ZEB1 or CD47. These results provide a rationale for an innovative preclinical combination immunotherapy based on PD-1/PD-L1 and CD47 blockade along with EMT inhibitors in patients with highly aggressive, mesenchymal, and metastatic breast cancer.