Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/Mena INV-initiated invadopodium formation

Jeanine Pignatelli, Jose Javier Bravo-Cordero, Minna Roh-Johnson, Saumil J. Gandhi, Yarong Wang, Xiaoming Chen, Robert J. Eddy, Alice Xue, Robert H. Singer, Louis Hodgson, Maja H. Oktay, John S. Condeelis

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Abstract

The process of intravasation involving transendothelial migration is a key step in metastatic spread. How the triple cell complex composed of a macrophage, Mena over-expressing tumor cell and endothelial cell, called the tumor microenvironment of metastasis (TMEM), facilitates tumor cell transendothelial migration is not completely understood. Previous work has shown that the physical contact between a macrophage and tumor cell results in the formation of invadopodia, actin-rich matrix degrading protrusions, important for tumor cell invasion and transendothelial migration and tumor cell dissemination. Herein, we show that the macrophage-induced invadopodium is formed through a Notch1/Mena INV signaling pathway in the tumor cell upon macrophage contact. This heterotypic tumor cell-macrophage interaction results in the upregulation of Mena INV through the activation of MENA transcription. Notch1 and Mena INV expression are required for tumor cell transendothelial migration, a necessary step during intravasation. Inhibition of the Notch signaling pathway blocked macrophage-induced invadopodium formation in vitro and the dissemination of tumor cells from the primary tumor in vivo. Our findings indicate a novel role for Notch1 signaling in the regulation of Mena INV expression and transendothelial migration and provide mechanistic information essential to the use of therapeutic inhibitors of metastasis.

Original languageEnglish (US)
Article number37874
JournalScientific Reports
Volume6
DOIs
StatePublished - Nov 30 2016

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Transendothelial and Transepithelial Migration
Cell Movement
Macrophages
Neoplasms
Podosomes
Neoplasm Metastasis
Tumor Microenvironment
Therapeutic Uses
Cell Communication
Transcriptional Activation
Actins
Up-Regulation
Endothelial Cells

ASJC Scopus subject areas

  • General

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Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/Mena INV-initiated invadopodium formation. / Pignatelli, Jeanine; Bravo-Cordero, Jose Javier; Roh-Johnson, Minna; Gandhi, Saumil J.; Wang, Yarong; Chen, Xiaoming; Eddy, Robert J.; Xue, Alice; Singer, Robert H.; Hodgson, Louis; Oktay, Maja H.; Condeelis, John S.

In: Scientific Reports, Vol. 6, 37874, 30.11.2016.

Research output: Contribution to journalArticle

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abstract = "The process of intravasation involving transendothelial migration is a key step in metastatic spread. How the triple cell complex composed of a macrophage, Mena over-expressing tumor cell and endothelial cell, called the tumor microenvironment of metastasis (TMEM), facilitates tumor cell transendothelial migration is not completely understood. Previous work has shown that the physical contact between a macrophage and tumor cell results in the formation of invadopodia, actin-rich matrix degrading protrusions, important for tumor cell invasion and transendothelial migration and tumor cell dissemination. Herein, we show that the macrophage-induced invadopodium is formed through a Notch1/Mena INV signaling pathway in the tumor cell upon macrophage contact. This heterotypic tumor cell-macrophage interaction results in the upregulation of Mena INV through the activation of MENA transcription. Notch1 and Mena INV expression are required for tumor cell transendothelial migration, a necessary step during intravasation. Inhibition of the Notch signaling pathway blocked macrophage-induced invadopodium formation in vitro and the dissemination of tumor cells from the primary tumor in vivo. Our findings indicate a novel role for Notch1 signaling in the regulation of Mena INV expression and transendothelial migration and provide mechanistic information essential to the use of therapeutic inhibitors of metastasis.",
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AU - Bravo-Cordero, Jose Javier

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AU - Gandhi, Saumil J.

AU - Wang, Yarong

AU - Chen, Xiaoming

AU - Eddy, Robert J.

AU - Xue, Alice

AU - Singer, Robert H.

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AU - Oktay, Maja H.

AU - Condeelis, John S.

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