TY - JOUR T1 - Tissue architectural cues drive the emergence of non-random trafficking of human tumor cells in the larval zebrafish JF - bioRxiv DO - 10.1101/233361 SP - 233361 AU - Colin D. Paul AU - Kevin Bishop AU - Alexus Devine AU - William J. Wulftange AU - Elliott L. Paine AU - Jack R. Staunton AU - Steven Shema AU - Val Bliskovsky AU - Lisa M. Miller Jenkins AU - Nicole Y. Morgan AU - Raman Sood AU - Kandice Tanner Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/12/13/233361.abstract N2 - Sites of metastasis are non-random, with certain types of cancers showing a preference of distal organ colonization. One fundamental question is what drives the emergence of organ selectivity. We determined that human breast tumor cells that home to specific murine organs migrated similarly within the circulatory system but ultimately colonized different organs in larval fish. Brain seeking clones homed preferentially to the brain, whereas bone seeking clones preferentially homed to the hematopoietic tissue in the tail (analogous to fetal mammalian bone marrow). Microenvironmental cues such as tissue mechanics and architecture are important regulators of tumorigenesis. We hypothesized that the physical properties of the tissue and vessel architecture drive the emergence of non-random targeting in the larval fish. We determined that vessel widths in the larval fish are on the scale of human capillaries with diverse architectures: ordered within the brain to disordered within the hematopoietic tissue. Both clones were occluded in each organ analog, where greater numbers accumulated in disordered blood vessels for organs that share similar tissue mechanics. Organ selectivity was an emergent phenomenon observed by 120 h post-injection following cell arrest. Functional blocking of integrin signaling redirected targeting of the bone-seeking clones. Our results show that specificity is driven by both occlusion and extravasation at the tumor-endothelial interface, in part regulated by integrin signaling and the vessel architecture. ER -