The netrin receptor DCC focuses invadopodia-driven basement membrane transmigration in vivo

Though critical to normal development and cancer metastasis, how cells traverse basement membranes is poorly understood. A central impediment has been the challenge of visualizing invasive cell interactions with basement membrane in vivo. By developing live-cell imaging methods to follow anchor cell...

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Bibliographic Details
Published in:The Journal of cell biology 2013-06, Vol.201 (6), p.903-913
Main Authors: Hagedorn, Elliott J, Ziel, Joshua W, Morrissey, Meghan A, Linden, Lara M, Wang, Zheng, Chi, Qiuyi, Johnson, Sam A, Sherwood, David R
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Animals, Genetically Modified
Basement Membrane - cytology
Basement Membrane - metabolism
Caenorhabditis elegans - cytology
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Caenorhabditis elegans Proteins - genetics
Caenorhabditis elegans Proteins - metabolism
Cell Adhesion Molecules - genetics
Cell Adhesion Molecules - metabolism
Cell Movement - physiology
Cells
Female
Genetics
Green Fluorescent Proteins - genetics
Membranes
Nematodes
Nerve Tissue Proteins - metabolism
Netrins
Pseudopodia - metabolism
Tissues
Vulva - cytology
Vulva - growth & development
Vulva - metabolism
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Summary:Though critical to normal development and cancer metastasis, how cells traverse basement membranes is poorly understood. A central impediment has been the challenge of visualizing invasive cell interactions with basement membrane in vivo. By developing live-cell imaging methods to follow anchor cell (AC) invasion in Caenorhabditis elegans, we identify F-actin-based invadopodia that breach basement membrane. When an invadopodium penetrates basement membrane, it rapidly transitions into a stable invasive process that expands the breach and crosses into the vulval tissue. We find that the netrin receptor UNC-40 (DCC) specifically enriches at the site of basement membrane breach and that activation by UNC-6 (netrin) directs focused F-actin formation, generating the invasive protrusion and the cessation of invadopodia. Using optical highlighting of basement membrane components, we further demonstrate that rather than relying solely on proteolytic dissolution, the AC's protrusion physically displaces basement membrane. These studies reveal an UNC-40-mediated morphogenetic transition at the cell-basement membrane interface that directs invading cells across basement membrane barriers.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201301091