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

Huimin Jiang,Hang Wang,Wei Sun,Chen Zhou,Quansheng Zhang,Wenhao Wang,Huimin Wei,Jianjun Li,Qiong Wang,Zhen Zhang,Peiqing Sun,Yang Ou,Zhaoyang Wang,Wen Shi,Shuang Yang

doi:10.1038/s41467-020-18860-4

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.

Highlights

Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs)
The number of Ki-67+ proliferating tumor cells and blood vessel density markedly decreased, whereas the spontaneous apoptosis rate and deposition of extracellular matrix increased in PyMT+/− mice (PyMT);Zeb1cKO mice (Supplementary Fig. 1a)
We previously reported that increased expression of Zeb[1] in breast cancer cells induces VEGFA production, promoting tumor angiogenesis and propagation[31]

Summary

Introduction

Zinc finger E-box binding homeobox 1 (Zeb1) has been demonstrated to participate in the acquisition of the properties of cancer stem cells (CSCs). It is largely unknown how signals from the tumor microenvironment (TME) contribute to aberrant Zeb[1] expression. We provide evidence that TME-derived endothelial Jag[1] elevates Zeb[1] expression in neighboring breast CSCs in a Notch1-mediated juxtacrine manner. Upregulation of Zeb[1] in tumor cells increases VEGFA production and reciprocally induces endothelial Jag[1] to create a positive feedback loop. Our data suggest that elucidating the microenvironmental signals (i.e., tumor perivascular niche) influencing aggressive breast cancer cells can provide effective treatment strategies

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Results

Conclusion