SPARC Promotes Cell Invasion In Vivo by Decreasing Type IV Collagen Levels in the Basement Membrane.
SPARC Promotes Cell Invasion In Vivo by Decreasing Type IV Collagen Levels in the Basement Membrane.
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DOI：
10.1371/journal.pgen.1005905
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发表时间：
2016-02
期刊：
影响因子：
4.5
通讯作者：
Sherwood DR
中科院分区：
文献类型：
--
作者：
Morrissey MA;Jayadev R;Miley GR;Blebea CA;Chi Q;Ihara S;Sherwood DR
Overexpression of SPARC, a collagen-binding glycoprotein, is strongly associated with tumor invasion through extracellular matrix in many aggressive cancers. SPARC regulates numerous cellular processes including integrin-mediated cell adhesion, cell signaling pathways, and extracellular matrix assembly; however, the mechanism by which SPARC promotes cell invasion in vivo remains unclear. A main obstacle in understanding SPARC function has been the difficulty of visualizing and experimentally examining the dynamic interactions between invasive cells, extracellular matrix and SPARC in native tissue environments. Using the model of anchor cell invasion through the basement membrane (BM) extracellular matrix in Caenorhabditis elegans, we find that SPARC overexpression is highly pro-invasive and rescues BM transmigration in mutants with defects in diverse aspects of invasion, including cell polarity, invadopodia formation, and matrix metalloproteinase expression. By examining BM assembly, we find that overexpression of SPARC specifically decreases levels of BM type IV collagen, a crucial structural BM component. Reduction of type IV collagen mimicked SPARC overexpression and was sufficient to promote invasion. Tissue-specific overexpression and photobleaching experiments revealed that SPARC acts extracellularly to inhibit collagen incorporation into BM. By reducing endogenous SPARC, we also found that SPARC functions normally to traffic collagen from its site of synthesis to tissues that do not express collagen. We propose that a surplus of SPARC disrupts extracellular collagen trafficking and reduces BM collagen incorporation, thus weakening the BM barrier and dramatically enhancing its ability to be breached by invasive cells. SPARC is an extracellular matrix protein that is present at high levels in many metastatic cancers where it promotes tumor invasion into neighboring tissues. The mechanism linking a surplus of SPARC to cell invasion, however, is not clear due to the challenge of examining SPARCs function in complex tumor environments. We have used anchor cell invasion in C. elegans development to understand how an excess of SPARC promotes invasion in a native tissue setting. Anchor cell invasion allows experimental examination and visualization of the interactions between an invasive cell, neighboring tissues, and the basement membrane, a sheet-like extracellular matrix that surrounds tissues. We find that increased SPARC expression potently enhances the ability of weakly invasive anchor cells to breach the basement membrane. Our data indicate that SPARC functions normally to transport the basement membrane component type IV collagen between tissues to precisely regulate its deposition into basement membranes. Collagen molecules are covalently cross-linked and provide basement membranes their barrier properties. Our results indicate that overexpression of SPARC interferes with collagen trafficking and significantly decreases collagen incorporation into basement membranes, potentially weakening this barrier and allowing it to be more easily breached by invasive cells.
