![]() We found that UNC-6/UNC-40 interactions localize lysosomes to the site of protrusion formation and that LMP-1 (a lysosomal protein) and ZMP-1 (a membrane-tethered MMP localized to lysosomes) are enriched in the invasive protrusion. Using quantitative live-cell imaging, genetic analysis, and misexpression studies, we examined the formation of the AC invasive protrusion. Together these studies define a netrin-dependent pathway that builds an invasive protrusion, an isolated lysosome-derived membrane structure specialized to breach tissue barriers. 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. 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. 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. Following the breach, a large protrusion forms to clear a path for tissue entry by poorly understood mechanisms. Invasive cells use small invadopodia to breach basement membrane (BM), a dense matrix that encases tissues.
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