3D Collagen Alignment Limits Protrusions to Enhance Breast Cancer Cell Persistence

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 tumo...

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Bibliographic Details
Published in:	Biophysical journal Vol. 107; no. 11; pp. 2546 - 2558
Main Authors:	Riching, Kristin M., Cox, Benjamin L., Salick, Max R., Pehlke, Carolyn, Riching, Andrew S., Ponik, Susan M., Bass, Benjamin R., Crone, Wendy C., Jiang, Yi, Weaver, Alissa M., Eliceiri, Kevin W., Keely, Patricia J.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 02-12-2014 Biophysical Society The Biophysical Society
Subjects:	Biophysics Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Biophysics Cell Line, Tumor Cell Movement Collagen Collagen - metabolism Extracellular Matrix - metabolism Female Gels Humans Mammography Models, Biological Oncology Stress response Tumors
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-3495 1542-0086
DOI:	10.1016/j.bpj.2014.10.035