Abstract

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.

Highlights

  • Cell invasion through extracellular matrix (ECM) is a critical step in the progression of many diseases including cancer metastasis [1,2]

  • Secreted Protein Acidic and Rich in Cysteine (SPARC) is an extracellular matrix protein that is present at high levels in many metastatic cancers where it promotes tumor invasion into neighboring tissues

  • We wanted to determine if SPARC overexpression might promote Anchor cell (AC) invasion in C. elegans

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Summary

Introduction

Cell invasion through extracellular matrix (ECM) is a critical step in the progression of many diseases including cancer metastasis [1,2]. Basement membrane (BM), a dense, sheet-like form of ECM that surrounds most tissues, poses a significant barrier for invasive cells [3]. Traditionally thought of as a static scaffold, changes to ECM composition, crosslinking, and stiffness can promote tumor progression by altering cell survival, growth, migration, or invasion [4,5]. BMs contain a number of associated proteins that link these networks, including nidogen and perlecan [6]. Helical collagen trimers assemble into a network through end-on and lateral attachments, including intermolecular covalent cross-links [1,7,8]. How the large collagen trimers (approximately 400 nm [14]) are trafficked and targeted to the BM is not well understood

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