Cell Invasion In Vivo via Rapid Exocytosis of a Transient Lysosome-Derived Membrane Domain

Publication date: 20 November 2017
Source:Developmental Cell, Volume 43, Issue 4
Author(s): Kaleb M. Naegeli, Eric Hastie, Aastha Garde, Zheng Wang, Daniel P. Keeley, Kacy L. Gordon, Ariel M. Pani, Laura C. Kelley, Meghan A. Morrissey, Qiuyi Chi, Bob Goldstein, David R. Sherwood
Invasive cells use small invadopodia to breach basement membrane (BM), a dense matrix that encases tissues. Following the breach, a large protrusion forms to clear a path for tissue entry by poorly understood mechanisms. Using RNAi screening for defects in Caenorhabditis elegans anchor cell (AC) invasion, we found that UNC-6(netrin)/UNC-40(DCC) signaling at the BM breach site directs exocytosis of lysosomes using the exocyst and SNARE SNAP-29 to form a large protrusion that invades vulval tissue. Live-cell imaging revealed that the protrusion is enriched in the matrix metalloprotease ZMP-1 and transiently expands AC volume by more than 20%, displacing surrounding BM and vulval epithelium. Photobleaching and genetic perturbations showed that the BM receptor dystroglycan forms a membrane diffusion barrier at the neck of the protrusion, which enables protrusion growth. Together these studies define a netrin-dependent pathway that builds an invasive protrusion, an isolated lysosome-derived membrane structure specialized to breach tissue barriers.

Graphical abstract

Teaser

How do invasive cells clear an entry path after basement membrane breach? Naegeli et al. show in Caenorhabditis elegans that directed lysosome exocytosis regulated by a netrin-mediated pathway builds the large invasive protrusion formed after invadopodia. Isolated by a dystroglycan membrane diffusion barrier, the protrusion expands to create tissue openings.


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