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. 2009 Jul 23;4(7):e6361.
doi: 10.1371/journal.pone.0006361.

Differential matrix rigidity response in breast cancer cell lines correlates with the tissue tropism

Ana Kostic  1 , Christopher D Lynch, Michael P Sheetz
Affiliations

Differential matrix rigidity response in breast cancer cell lines correlates with the tissue tropism

Ana Kostic et al. PLoS One. .

Abstract

Metastasis to a variety of distant organs, such as lung, brain, bone, and liver, is a leading cause of mortality in the breast cancer patients. The tissue tropism of breast cancer metastasis has been recognized and studied extensively, but the cellular processes underlying this phenomenon, remain elusive. Modern technologies have enabled the discovery of a number of the genetic factors determining tissue tropism of malignant cells. However, the effect of these genetic differences on the cell motility and invasiveness is poorly understood. Here, we report that cellular responses to the mechanical rigidity of the extracellular matrix correlate with the rigidity of the _target tissue. We tested a series of single cell populations isolated from MDA-MB-231 breast cancer cell line in a variety of assays where the extracellular matrix rigidity was varied to mimic the environment that these cells might encounter in vivo. There was increased proliferation and migration through the matrices of rigidities corresponding to the native rigidities of the organs where metastasis was observed. We were able to abolish the differential matrix rigidity response by knocking down Fyn kinase, which was previously identified as a critical component of the FN rigidity response pathway in healthy cells. This result suggests possible molecular mechanisms of the rigidity response in the malignant cells, indicating potential candidates for therapeutic interventions.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Collagen rigidity differentially affects proliferation of the various SCPs.
(A-D) Breast cancer cell lines SCP 2, SCP3, SCP21, and breast epithelial cell lines MCF10A were plated on rigid and soft collagen-coated polyacrylamide gels and their proliferation was observed over the time period of 72 h. (E) Representative morphology of SCP 2, SCP3, SCP21, and MCF10A cells after 72 h incubation on soft and rigid collagen-coated gels. (F) Chart of the collagen rigidity response in SCP 2, SCP3, SCP21, SCP26, SCP28, SCP32, SCP39, SCP46, and breast epithelial cell line MCF10A and their specific in vivo tissue tropisms.
Figure 2
Figure 2. Fibronectin rigidity differentially affects proliferation of the various SCPs.
(A-D) Breast cancer cell lines SCP 2, SCP3, SCP21, and breast epithelial cell lines MCF10A were plated on rigid and soft FN-coated polyacrylamide gels and their proliferation was observed over the time period of 72 h. (E) Representative morphology of SCP 2, SCP3, SCP21, and MCF10A cells after 72 h incubation on soft and rigid FN-coated gels (F) Chart of the FN rigidity response in SCP 2, SCP3, SCP21, SCP26, SCP28, SCP32, SCP39, SCP46, and breast epithelial cell line MCF10A and their specific in vivo tissue tropisms.
Figure 3
Figure 3. Fyn is required for survival of bone-specific SCPs on rigid FN-coated matrices.
(A-D) Breast cancer cell lines SCP 2, SCP3, SCP21, and breast epithelial cell line MCF10A treated with Fyn siRNA were plated on rigid and soft FN-coated polyacrylamide gels and their proliferation was observed over the time period of 72 h. (E) Representative morphology of Fyn siRNA-treated SCP 2, SCP3, SCP21, and MCF10A cells after 72 h incubation on soft and rigid FN-coated gels (F) Chart of the effect of Fyn knockdown on the rigidity response in SCP 2, SCP3, SCP21, SCP26, SCP28, SCP32, SCP39, SCP46, and breast epithelial cell line MCF10A. Their original in vivo tissue tropisms are also shown.
Figure 4
Figure 4. Transwell migration of various SCPs in differentially dependent on matrix rigidity.
(A) Transwell system used consists of the upper chambers containg a thin layer of FN-enriched matrigel, perforated membrane, and the lower chamber coated with FN. (B-C) Breast cancer cell lines SCP 2, SCP3, SCP21, SCP26, SCP28, SCP32, SCP39, SCP46, and breast epithelial cell lines MCF10A were plated in matrigel pf increasing rigidities and their transwell migration rates were quantified after 48 h incubation.
Figure 5
Figure 5. Matrix rigidity has no significant effect on spreading areas of the SCPs.
(A-B) Breast cancer cell lines SCP 2, SCP3, SCP21, SCP26, SCP28, SCP32, SCP39, SCP46, and breast epithelial cell line MCF10A were allowed to spread on rigid and soft collagen-coated (A) or FN-coated (B) polyacrylamide gels for 2 h, when the spreading areas were quantified.
Figure 6
Figure 6. Early spreading motility appears uniform among different SCPs.
(A-D) Breast epithelial cell line MCF10A (A), and breast cancer cell lines SCP 2 (B), SCP3 (C), and SCP21 (D) were plated on FN-coated glass and their spreading was recorded. The timecourse of representative cells is shown. No significant changes in cell area or motility were observed in cells that were observed longer than 20 min (up to 2 h). (E) Time dependence of the avareage spread area in SCP 2, SCP3, SCP21, and MCF10A cells. (F) Average spreading rates were calculated for 5 min time periods to quantify early spreading velocities in SCP 2, SCP3, SCP21, and MCF10A cells.
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