Localized ATP production and F-actin polymerization drive basement membrane invasion in the absence of MMPs
| Dates: | 8 December 2017 |
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| Times: | 13:00 - 14:00 |
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| What is it: | Seminar |
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| Organiser: | Faculty of Biology, Medicine and Health |
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| Who is it for: | University staff, Current University students |
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| Speaker: | David R. Sherwood |
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The ability of cells to breach basement membrane barriers—thin, dense, sheets of extracellular matrix that underlie most tissues—is important in development, wound healing, leukocyte trafficking, and metastasis. To understand the mechanisms that control invasion, our lab is using the model system of anchor cell (AC) invasion into the vulval epithelium in C. elegans, an optically transparent organism that allows genetic and visual analysis of basement membrane invasion. Like invasive human cancer cells, the AC breaches basement membrane with small, protrusive, F-actin rich membrane associated structures, termed invadopodia. Using this model for cell invasion, we are investigating the requirements of matrix metalloproteinases (MMPs). MMPs are a class of proteases strongly implicated in promoting invasion in many cancers, and have been targeted in extensive clinical trials in patients with metastasis. These therapeutic trials failed, however, for unclear reasons. We have found that the AC expresses three MMPs (ZMP-1, -3, and -6) at the time of invasion. Surprisingly, the AC stills invades after genetic removal of these MMPs, although in a slightly delayed manner. Using time-lapse analysis, whole genome RNAi screens, and optical highlighting approaches, we found that the AC invades in MMP(-) animals by physically breaking through the basement membrane. Striking, we discovered that F-actin production is increased in the absence of MMPs, and mitochondria and ATP localize strongly to the site of invasion. Reduction of F-actin polymerization or ATP generation strongly blocks invasion in MMP(-) animals, but not in wild type animals. Together, these observations suggest that basement membrane invasion programs are highly robust and adaptive--in the absence of MMPs, mitochondria polarize to the site of invasion and provide a localized source of ATP that allows increased F-actin formation and basement membrane breaching. These results may help explain the failure of clinical trials targeting MMPs and suggest possible therapies to specifically target invading cells.
Speaker
David R. Sherwood
Organisation: Department of Biology, Duke University, Durham, NC, USA
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Lecture Theatre
Michael Smith Building
Manchester
