title: 3D collagen alignment limits protrusions to enhance breast cancer cell persistence.
abstract: Patients with mammographically dense breast tissue have a greatly increased risk of developing breast cancer. Dense breast tissue contains more stromal collagen, which contributes to increased matrix stiffness and alters normal cellular responses. Stromal collagen within and surrounding mammary tumors is frequently aligned and reoriented perpendicular to the tumor boundary. We have shown that aligned collagen predicts poor outcome in breast cancer patients, and postulate this is because it facilitates invasion by providing tracks on which cells migrate out of the tumor. However, the mechanisms by which alignment may promote migration are not understood. Here, we investigated the contribution of matrix stiffness and alignment to cell migration speed and persistence. Mechanical measurements of the stiffness of collagen matrices with varying density and alignment were compared with the results of a 3D microchannel alignment assay to quantify cell migration. We further interpreted the experimental results using a computational model of cell migration. We find that collagen alignment confers an increase in stiffness, but does not increase the speed of migrating cells. Instead, alignment enhances the efficiency of migration by increasing directional persistence and restricting protrusions along aligned fibers, resulting in a greater distance traveled. These results suggest that matrix topography, rather than stiffness, is the dominant feature by which an aligned matrix can enhance invasion through 3D collagen matrices.
authors.affiliation: Biomedical Engineering Program, University of Wisconsin-Madison, Madison, Wisconsin; Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Riching
authors.affiliation: Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin; Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Cox
authors.affiliation: Materials Science Program, University of Wisconsin-Madison, Madison, Wisconsin; Department of Engineering Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Max R
authors.initials: MR
authors.lastname: Salick
authors.affiliation: Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Pehlke
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Riching
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ponik
authors.affiliation: Saris Cycling Group, Madison, Wisconsin.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Bass
authors.affiliation: Biomedical Engineering Program, University of Wisconsin-Madison, Madison, Wisconsin; Materials Science Program, University of Wisconsin-Madison, Madison, Wisconsin; Department of Engineering Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Crone
authors.affiliation: Department of Mathematics and Statistics, Georgia State University, Atlanta, Georgia.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: Weaver
authors.affiliation: Biomedical Engineering Program, University of Wisconsin-Madison, Madison, Wisconsin; Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Biomedical Engineering Program, University of Wisconsin-Madison, Madison, Wisconsin; Laboratory for Optical and Computational Instrumentation, University of Wisconsin-Madison, Madison, Wisconsin; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, Wisconsin; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin. Electronic address: pjkeely@wisc.edu.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005782:Gels; D006801:Humans; D008954:Models, Biological
chemical_list: D005782:Gels; D003094:Collagen