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Sci Rep. 2018 Sep 21;8(1):14210. doi: 10.1038/s41598-018-32010-3.

Biomechanical interplay between anisotropic re-organization of cells and the surrounding matrix underlies transition to invasive cancer spread.

Kim DH1,2, Ewald AJ3,4,5, Park J6,7, Kshitiz8,3,6,7, Kwak M9, Gray RS4, Su CY8, Seo J10, An SS11,12,13, Levchenko A14,15,16.

Author information

1
Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA. deokho@uw.edu.
2
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. deokho@uw.edu.
3
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
4
Department of Cell Biology, Johns Hopkins University, Baltimore, MD, 21218, USA.
5
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
6
Department of Biomedical Engineering, Yale University, New Haven, CT, 06520, USA.
7
Yale Systems Biology Institute, Yale University, West Haven, CT, 06516, USA.
8
Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.
9
School of Mechanical Engineering, Kyungpook National University, Daegu, 41566, Korea.
10
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA.
11
Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. san@jhu.edu.
12
Department of Chemical and Biomolecular Engineering, Johns Hopkins Whiting School of Engineering, Baltimore, MD, 21218, USA. san@jhu.edu.
13
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. san@jhu.edu.
14
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA. andre.levchenko@yale.edu.
15
Department of Biomedical Engineering, Yale University, New Haven, CT, 06520, USA. andre.levchenko@yale.edu.
16
Yale Systems Biology Institute, Yale University, West Haven, CT, 06516, USA. andre.levchenko@yale.edu.

Abstract

The root cause of cancer mortality and morbidity is the metastatic spread of the primary tumor, but underlying mechanisms remain elusive. Here we investigate biomechanical interactions that may accompany invasive spread of melanoma cells. We find that metastatic cells can exert considerable traction forces and modify local collagen organization within a 3D matrix. When this re-organization is mimicked using a nano-fabricated model of aligned extracellular matrix fibers, metastatic cells, including less invasive melanoma cells, were in turn induced to align, elongate and migrate, guided by the local ridge orientations. Strikingly, we found that this aligned migration of melanoma cells was accompanied by long-range regulation of cytoskeletal remodeling that show anisotropic stiffening in the direction of fiber orientation suggestive of a positive feedback between ECM fiber alignment and forces exerted by cancer cells. Taken together, our findings suggest that the invasive spread of cancer cells can be defined by complex interplay with the surrounding matrix, during which they both modify the matrix and use the matrix alignment as a persistent migration cue, leading to more extensive and rapid invasive spread.

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