title: Soft matrix is a natural stimulator for cellular invasiveness.
abstract: Directional mesenchymal cell invasion in vivo is understood to be a stimulated event and to be regulated by cytokines, chemokines, and types of extracellular matrix (ECM). Instead, by focusing on the cellular response to ECM stiffness, we found that soft ECM (low stiffness) itself is sufficient to prevent stable cell-to-cell adherens junction formation, up-regulate matrix metalloproteinase (MMP) secretion, promote MMP activity, and induce invadosome-like protrusion (ILP) formation. Consistently, similar ILP formation was also detected in a three-dimensional directional invasion assay in soft matrix. Primary human fibroblasts spontaneously form ILPs in a very narrow range of ECM stiffness (0.1-0.4 kPa), and such ILP formation is Src family kinase dependent. In contrast, spontaneous ILP formation in malignant cancer cells and fibrosarcoma cells occurs across a much wider range of ECM stiffness, and these tumor cell ILPs are also more prominent at lower stiffness. These findings suggest that ECM softness is a natural stimulator for cellular invasiveness.
authors: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054 Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905.
authors: Zhizhan
authors: Z
authors: Gu
authors: Fei
authors: F
authors: Liu
authors: Elina A
authors: EA
authors: Tonkova
authors: Soo Young
authors: SY
authors: Lee
authors: Daniel J
authors: DJ
authors: Tschumperlin
authors: Michael B
authors: MB
authors: Brenner
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism* / Q000648:ultrastructure; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism* / Q000648:ultrastructure; D004548:Elasticity; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006244:Hardness; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D009361:Neoplasm Invasiveness; D061251:Primary Cell Culture; D013499:Surface Properties; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D019061:src-Family Kinases; D020782:Matrix Metalloproteinases