title: Enhanced Directional Migration of Cancer Stem Cells in 3D Aligned Collagen Matrices.
abstract: Directed cell migration by contact guidance in aligned collagenous extracellular matrix (ECM) is a critical enabler of breast cancer dissemination. The mechanisms of this process are poorly understood, particularly in 3D, in part because of the lack of efficient methods to generate aligned collagen matrices. To address this technological gap, we propose a simple method to align collagen gels using guided cellular compaction. Our method yields highly aligned, acellular collagen constructs with predictable microstructural features, thus providing a controlled microenvironment for in vitro experiments. Quantifying cell behavior in these anisotropic constructs, we find that breast carcinoma cells are acutely sensitive to the direction and extent of collagen alignment. Further, live cell imaging and analysis of 3D cell migration reveals that alignment of collagen does not alter the total motility of breast cancer cells, but simply redirects their migration to produce largely one-dimensional movement. However, a profoundly enhanced motility in aligned collagen matrices is observed for the subpopulation of carcinoma cells with high tumor initiating and metastatic capacity, termed cancer stem cells (CSCs). Analysis of the biophysical determinants of cell migration show that nuclear deformation is not a critical factor associated with the observed increases in motility for CSCs. Rather, smaller cell size, a high degree of phenotypic plasticity, and increased protrusive activity emerge as vital facilitators of rapid, contact-guided migration of CSCs in aligned 3D collagen matrices.
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota; University of Minnesota Physical Sciences in Oncology Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Arja
authors.initials: A
authors.lastname: Ray
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Slama
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota; University of Minnesota Physical Sciences in Oncology Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Morford
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Madden
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota; University of Minnesota Physical Sciences in Oncology Center, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota; Institute for Engineering in Medicine, University of Minnesota, Minneapolis, Minnesota. Electronic address: pprovenz@umn.edu.
authors.forename: Paolo P
authors.initials: PP
authors.lastname: Provenzano
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype
chemical_list: D003094:Collagen