Degradation and Remodeling of Epitaxially Grown Collagen Fibrils
The extracellular matrix (ECM) in the tumor microenvironment contains high densities of collagen that are highly aligned, resulting in directional migration called contact guidance that facilitates efficient migration out of the tumor. Cancer cells can remodel the ECM through traction force controlled by myosin contractility or proteolytic activity controlled by matrix metalloproteinase (MMP) activity, leading to either enhanced or diminished contact guidance.
Recently, we have leveraged the ability of mica to epitaxially grow aligned collagen fibrils in order to assess contact guidance. In this article, we probe the mechanisms of remodeling of aligned collagen fibrils on mica by breast cancer cells.
We show that cells that contact guide with high fidelity (MDA-MB-231 cells) exert more force on the underlying collagen fibrils than do cells that contact guide with low fidelity (MTLn3 cells). These high traction cells (MDA-MB-231 cells) remodel collagen fibrils over hours, pulling so hard that the collagen fibrils detach from the surface, effectively delaminating the entire contact guidance cue. Myosin or MMP inhibition decreases this effect. Interestingly, blocking MMP appears to increase the alignment of cells on these substrates, potentially allowing the alignment through myosin contractility to be uninhibited. Finally, amplification or dampening of contact guidance with respect to a particular collagen fibril organization is seen under different conditions.
Both myosin II contractility and MMP activity allow MDA-MB-231 cells to remodel and eventually destroy epitaxially grown aligned collagen fibrils.
KeywordsDirected migration Second harmonic generation MT1-MMP MMP-14 Function blocking antibody
Second harmonic generation
Tissue inhibitor of matrix metalloproteinase
Dulbecco’s modified Eagles medium
Fetal bovine serum
Honest significant difference
We acknowledge Zhiqi Yao and Andrew Hillier with help on the AFM imaging and Jacob Nuhn for help with the MMP assays.
This work was supported by the National Institutes of Health/National Institute for General Medical Sciences [R01GM115672]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Conflict of interest
Juan Wang, Anuraag Boddupalli, Joseph Koelbl, Dong Hyun Nam, Xin Ge, Kaitlin M. Bratlie and Ian C. Schneider state they have no conflicts of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
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