Anna Haeger1, Marina Krause2, Katarina Wolf2, Peter Friedl3. 1. Radboud Institute for Molecular Life Sciences, Department of Cell Biology, Post 283, PO Box 9101, 6500HB Nijmegen, The Netherlands. Electronic address: a.haeger@ncmls.ru.nl. 2. Radboud Institute for Molecular Life Sciences, Department of Cell Biology, Post 283, PO Box 9101, 6500HB Nijmegen, The Netherlands. 3. Radboud Institute for Molecular Life Sciences, Department of Cell Biology, Post 283, PO Box 9101, 6500HB Nijmegen, The Netherlands; UT MD Anderson Cancer Center, Genitourinary Medical Oncology-Research, Houston TX, USA; Cancer Genomics Center, The Netherlands. Electronic address: p.friedl@ncmls.ru.nl.
Abstract
BACKGROUND: Cancer invasion is a multi-step process which coordinates interactions between tumor cells with mechanotransduction towards the surrounding matrix, resulting in distinct cancer invasion strategies. Defined by context, mesenchymal tumors, including melanoma and fibrosarcoma, develop either single-cell or collective invasion modes, however, the mechanical and molecular programs underlying such plasticity of mesenchymal invasion programs remain unclear. METHODS: To test how tissue anatomy determines invasion mode, spheroids of MV3 melanoma and HT1080 fibrosarcoma cells were embedded into 3D collagen matrices of varying density and stiffness and analyzed for migration type and efficacy with matrix metalloproteinase (MMP)-dependent collagen degradation enabled or pharmacologically inhibited. RESULTS: With increasing collagen density and dependent on proteolytic collagen breakdown and track clearance, but independent of matrix stiffness, cells switched from single-cell to collective invasion modes. Conversion to collective invasion included gain of cell-to-cell junctions, supracellular polarization and joint guidance along migration tracks. CONCLUSIONS: The density of the extracellulair matrix (ECM) determines the invasion mode of mesenchymal tumor cells. Whereas fibrillar, high porosity ECM enables single-cell dissemination, dense matrix induces cell-cell interaction, leader-follower cell behavior and collective migration as an obligate protease-dependent process. GENERAL SIGNIFICANCE: These findings establish plasticity of cancer invasion programs in response to ECM porosity and confinement, thereby recapitulating invasion patterns of mesenchymal tumors in vivo. The conversion to collective invasion with increasing ECM confinement supports the concept of cell jamming as a guiding principle for melanoma and fibrosarcoma cells into dense tissue. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
BACKGROUND:Cancer invasion is a multi-step process which coordinates interactions between tumor cells with mechanotransduction towards the surrounding matrix, resulting in distinct cancer invasion strategies. Defined by context, mesenchymal tumors, including melanoma and fibrosarcoma, develop either single-cell or collective invasion modes, however, the mechanical and molecular programs underlying such plasticity of mesenchymal invasion programs remain unclear. METHODS: To test how tissue anatomy determines invasion mode, spheroids of MV3 melanoma and HT1080 fibrosarcoma cells were embedded into 3D collagen matrices of varying density and stiffness and analyzed for migration type and efficacy with matrix metalloproteinase (MMP)-dependent collagen degradation enabled or pharmacologically inhibited. RESULTS: With increasing collagen density and dependent on proteolytic collagen breakdown and track clearance, but independent of matrix stiffness, cells switched from single-cell to collective invasion modes. Conversion to collective invasion included gain of cell-to-cell junctions, supracellular polarization and joint guidance along migration tracks. CONCLUSIONS: The density of the extracellulair matrix (ECM) determines the invasion mode of mesenchymal tumor cells. Whereas fibrillar, high porosity ECM enables single-cell dissemination, dense matrix induces cell-cell interaction, leader-follower cell behavior and collective migration as an obligate protease-dependent process. GENERAL SIGNIFICANCE: These findings establish plasticity of cancer invasion programs in response to ECM porosity and confinement, thereby recapitulating invasion patterns of mesenchymal tumors in vivo. The conversion to collective invasion with increasing ECM confinement supports the concept of cell jamming as a guiding principle for melanoma and fibrosarcoma cells into dense tissue. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
Authors: S K Ranamukhaarachchi; R N Modi; A Han; D O Velez; A Kumar; A J Engler; S I Fraley Journal: Biomater Sci Date: 2019-01-29 Impact factor: 6.843
Authors: Medhavi Vishwakarma; Basil Thurakkal; Joachim P Spatz; Tamal Das Journal: Philos Trans R Soc Lond B Biol Sci Date: 2020-07-27 Impact factor: 6.237
Authors: David G Menter; Scott Kopetz; Ernest Hawk; Anil K Sood; Jonathan M Loree; Paolo Gresele; Kenneth V Honn Journal: Cancer Metastasis Rev Date: 2017-06 Impact factor: 9.264
Authors: Jian Zhang; Kayla F Goliwas; Wenjun Wang; Paul V Taufalele; Francois Bordeleau; Cynthia A Reinhart-King Journal: Proc Natl Acad Sci U S A Date: 2019-03-28 Impact factor: 11.205