ZEB1-repressed microRNAs inhibit autocrine signaling that promotes vascular mimicry of breast cancer cells

Oncogene
E M LangerR C Sears

Abstract

During normal tumor growth and in response to some therapies, tumor cells experience acute or chronic deprivation of nutrients and oxygen and induce tumor vascularization. While this occurs predominately through sprouting angiogenesis, tumor cells have also been shown to directly contribute to vessel formation through vascular mimicry (VM) and/or endothelial transdifferentiation. The extrinsic and intrinsic mechanisms underlying tumor cell adoption of endothelial phenotypes, however, are not well understood. Here we show that serum withdrawal induces mesenchymal breast cancer cells to undergo VM and that knockdown of the epithelial-to-mesenchymal transition (EMT) regulator, Zinc finger E-box binding homeobox 1 (ZEB1), or overexpression of the ZEB1-repressed microRNAs (miRNAs), miR-200c, miR-183, miR-96 and miR-182 inhibits this process. We find that secreted proteins Fibronectin 1 (FN1) and serine protease inhibitor (serpin) family E member 2 (SERPINE2) are essential for VM in this system. These secreted factors are upregulated in mesenchymal cells in response to serum withdrawal, and overexpression of VM-inhibiting miRNAs abrogates this upregulation. Intriguingly, the receptors for these secreted proteins, low-density lipoprot...Continue Reading

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Mar 15, 2020·Stem Cells Translational Medicine·Anastasia C HepburnRakesh Heer
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Datasets Mentioned

BETA
GSE77179
GSE26524

Methods Mentioned

BETA
flow cytometry
RNA-seq
transfection
PCR
FACS
RNAseq
electrophoresis
xenograft

Software Mentioned

fastq
Step One
Step One Real Time PCR
Gene Set Enrichment Analysis
FlowJo
ImageJ
Zeiss Zen
custom R
IncuCyte
FACS Diva

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