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

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.

Deficiency of Mettl3 in Bladder Cancer Stem Cells Inhibits Bladder Cancer Progression and Angiogenesis

“…Previous study has shown Ang2-TEK signaling as a key regulator in lymphogenous metastasis ( Gengenbacher et al, 2020 ). VEGF-A as a downstream factor of Zeb1 enhances breast cancer cells’ aggressiveness through sustaining stemness ( Jiang et al, 2020 ). Indeed, the regulatory networks of epigenomics, angiogenesis, and stemness maintenance are intricate.…”

Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

“…Notch signaling is often activated in cancer cells that show enhanced stem cell maintenance. Notch-positive CSCs have recently been shown to be preferentially associated with endothelial cells within the tumor tissue, which is likely to act as a perivascular stem cell niche in breast cancer [ 84 , 85 ]. It was shown that tight association of quiescent cancer cells with an effective stem cell niche can significantly contribute to tumor dormancy and protect CSCs from therapeutic interventions such as chemo- and radiotherapy [ 84 ].…”

“…It was shown that tight association of quiescent cancer cells with an effective stem cell niche can significantly contribute to tumor dormancy and protect CSCs from therapeutic interventions such as chemo- and radiotherapy [ 84 ]. A similar perivascular stem cell niche for the persistence of CSC has recently been characterized in detail, and found to be promoted by active Jagged-1-Notch-1 signaling [ 84 , 85 ]. The Notch-dependent response in these CSCs involves the upregulation of ZEB1 in a positive feedback loop and stimulates endothelial cells by paracrine production of VEGFA.…”

“…The Notch-dependent response in these CSCs involves the upregulation of ZEB1 in a positive feedback loop and stimulates endothelial cells by paracrine production of VEGFA. Disrupting the cycle, e.g., by ZEB1 deletion, decreases tumorigenesis and progression in vivo [ 85 ]. The mechanisms by which Notch signaling may promote stemness are certainly complex and may also involve additional cell types other than endothelial cells.…”

“…Like the NOTCH receptors, Notch ligands are also related to the induction of EMT in cancer. Elevated expression of JAG1 correlates with poor prognosis in many cancer type [ 85 , 141 , 142 ]. Notch activation via both DLL and JAG ligands leads to induction of EMT, and interaction with Jagged increased the formation of cell clusters, a specific phenotype that could be stabilized by Numb or Numbl proteins [ 139 , 143 ].…”