title: Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/MenaINV-initiated invadopodium formation.
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/MenaINVsignaling pathway in the tumor cell upon macrophage contact. This heterotypic tumor cell - macrophage interaction results in the upregulation of MenaINVthrough the activation of MENA transcription. Notch1 and MenaINVexpression 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 MenaINVexpression and transendothelial migration and provide mechanistic information essential to the use of therapeutic inhibitors of metastasis.
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.|Gruss Lipper Biophotonics Center Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Pignatelli
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.|Gruss Lipper Biophotonics Center Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Bravo-Cordero
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.|Gruss Lipper Biophotonics Center Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Minna
authors.initials: M
authors.lastname: Roh-Johnson
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Saumil J
authors.initials: SJ
authors.lastname: Gandhi
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.|Gruss Lipper Biophotonics Center Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Eddy
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Alice
authors.initials: A
authors.lastname: Xue
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Singer
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.|Gruss Lipper Biophotonics Center Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: Hodgson
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.|Department of Pathology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: Maja H
authors.initials: MH
authors.lastname: Oktay
authors.affiliation: Department of Anatomy and Structural Biology Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.|Gruss Lipper Biophotonics Center Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Condeelis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D000069261:Podosomes / Q000378:metabolism* / Q000502:physiology; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D008840:Microfilament Proteins; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1