Jagged1-Notch1-deployed tumor perivascular niche promotes breast cancer stem cell phenotype through Zeb1

Huimin Jiang, Chen Zhou, Zhen Zhang, Qiong Wang, Huimin Wei, Wen Shi, Jianjun Li, Zhaoyang Wang, Yang Ou, Wenhao Wang, Hang Wang, Quansheng Zhang, Wei Sun, Peiqing Sun and Shuang Yang ()
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Huimin Jiang: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Chen Zhou: Xuanwu Hospital, Capital Medical University
Zhen Zhang: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Qiong Wang: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Huimin Wei: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Wen Shi: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Jianjun Li: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Zhaoyang Wang: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Yang Ou: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Wenhao Wang: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Hang Wang: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Quansheng Zhang: Tianjin Key Laboratory of Organ Transplantation, Tianjin First Center Hospital
Wei Sun: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University
Peiqing Sun: Wake Forest University School of Medicine
Shuang Yang: Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs). However, it is largely unknown how signals from the tumor microenvironment (TME) contribute to aberrant Zeb1 expression. Here, we show that Zeb1 depletion suppresses stemness, colonization and the phenotypic plasticity of breast cancer. Moreover, we demonstrate that, with direct cell-cell contact, TME-derived endothelial cells provide the Notch ligand Jagged1 (Jag1) to neighboring breast CSCs, leading to Notch1-dependent upregulation of Zeb1. In turn, ectopic Zeb1 in tumor cells increases VEGFA production and reciprocally induces endothelial Jag1 in a paracrine manner. Depletion of Zeb1 disrupts this positive feedback loop in the tumor perivascular niche, which eventually lessens tumor initiation and progression in vivo and in vitro. In this work, we highlight that targeting the angiocrine Jag1-Notch1-Zeb1-VEGFA loop decreases breast cancer aggressiveness and thus enhances the efficacy of antiangiogenic therapy.

Date: 2020
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DOI: 10.1038/s41467-020-18860-4

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