title: Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors.
abstract: Metastasis is the main cause of death in breast cancer patients. Cell migration is an essential component of almost every step of the metastatic cascade, especially the early step of invasion inside the primary tumor. In this report, we have used intravital multiphoton microscopy to visualize the different migration patterns of human breast tumor cells in live primary tumors. We used xenograft tumors of MDA-MB-231 cells as well as a low passage xenograft tumor from orthotopically injected patient-derived breast tumor cells. Direct visualization of human tumor cells in vivo shows two patterns of high-speed migration inside primary tumors: (1) single cells and (2) multicellular streams (i.e., cells following each other in a single file but without cohesive cell junctions). Critically, we found that only streaming and not random migration of single cells was significantly correlated with proximity to vessels, with intravasation and with numbers of elevated circulating tumor cells in the bloodstream. Finally, although the two human tumors were derived from diverse genetic backgrounds, we found that their migratory tumor cells exhibited coordinated gene expression changes that led to the same end-phenotype of enhanced migration involving activating actin polymerization and myosin contraction. Our data are the first direct visualization and assessment of in vivo migration within a live patient-derived breast xenograft tumor.
authors.affiliation: Department of Anatomy and Structural Biology; Albert Einstein College of Medicine; Bronx, NY USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Patsialou
authors.affiliation: Department of Anatomy and Structural Biology; Albert Einstein College of Medicine; Bronx, NY USA ; Gruss Lipper Biophotonics Center; Albert Einstein College of Medicine; Bronx, NY USA.
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Bravo-Cordero
authors.affiliation: Department of Anatomy and Structural Biology; Albert Einstein College of Medicine; Bronx, NY USA.
authors.forename: Yarong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Gruss Lipper Biophotonics Center; Albert Einstein College of Medicine; Bronx, NY USA.
authors.forename: David
authors.initials: D
authors.lastname: Entenberg
authors.affiliation: The Ben May Department for Cancer Research; University of Chicago; Chicago, IL USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Liu
authors.affiliation: The Institute for Stem Cell Biology and Regenerative Medicine; Stanford University; Palo Alto, CA USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Clarke
authors.affiliation: Department of Anatomy and Structural Biology; Albert Einstein College of Medicine; Bronx, NY USA ; Gruss Lipper Biophotonics Center; Albert Einstein College of Medicine; Bronx, NY USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Condeelis
keywords: breast cancer; invasion; migration; multicellular streaming; multiphoton imaging