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Collagen Stiffness Modulates MDA-MB231 Cell Metabolism Through Adhesion-Mediated Contractility

48 Pages Posted: 7 Jun 2018 Sneak Peek Status: Under Review

See all articles by Emma J. Mah

Emma J. Mah

University of California, Irvine - Department of Chemical Engineering and Materials Science

Gabrielle E. McGahey

University of California, Irvine - Department of Biomedical Engineering

Albert F. Yee

University of California, Irvine - Department of Chemical Engineering and Materials Science; University of California, Irvine - Department of Biomedical Engineering

Michelle A. Digman

University of California, Irvine - Department of Chemical Engineering and Materials Science; University of California, Irvine - Department of Biomedical Engineering; University of California, Irvine - Laboratory for Fluorescence Dynamics (LFD)

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Abstract

Extracellular matrix (ECM) mechanical properties play a key role in cancer cell aggressiveness. Increasing substrate stiffness upregulates cancer invasion, cell contractility and focal adhesion formation. In addition to matrix properties, alteration in energy metabolism is a known characteristic of cancer cells (i.e., Warburg effect) and modulates cell invasion. However, there has been little evidence to show that substrate stiffness is able to affect cancer cell metabolism. Thus, we investigated changes in energy metabolism in response to varying collagen matrix stiffness in different cancer cells, MDA-MB231, AA375MM and U251MG and non- tumorigenic breast cell line MCF10A. Using the phasor approach to fluorescent lifetime imaging microscopy (FLIM), we measured the lifetime ratio of the free:bound state of NADH and determined if these cells altered their metabolism when plated on varying ECM density. This approach is a powerful tool that allows us to map the metabolic trajectory of each living cell within its cellular compartments. In our studies, we found that MDA-MB231 cells had an increase in bound NADH, indicating oxidative phosphorylation (OXPHOS), as collagen substrate density decreased. When inhibiting myosin-II contractility with Y-27632 or blebbistatin, the MDA-MB231 cells on glass shifted from glycolysis (GLY) to OXPHOS, confirming the intricate relationship between mechanosensing and metabolism in these highly invasive tumor cells. The human glioblastoma cell line, U251MG, showed an opposite trend compared to the invasive MDA-MB231 cells. However, the human melanoma cell line, A375MM did not show any significant changes in metabolic indices when they were grown on surfaces with varying collagen density but changed when grown on glass surfaces. MCF10A cells showed no changes in metabolism across all surfaces. In addition, OXPHOS or GLY inhibitors to MDA-MB231 cells showed dramatic shifts from OXPHOS to GLY or vice versa. There were slight changes detected in MCF10A cells. These results provide an important link between cellular metabolism, contractility and ECM stiffness in human breast cancer.

Suggested Citation

Mah, Emma J. and McGahey, Gabrielle E. and Yee, Albert F. and Digman, Michelle A., Collagen Stiffness Modulates MDA-MB231 Cell Metabolism Through Adhesion-Mediated Contractility (2018). Available at SSRN: https://ssrn.com/abstract=3188427 or http://dx.doi.org/10.2139/ssrn.3188427
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Emma J. Mah

University of California, Irvine - Department of Chemical Engineering and Materials Science

916 Engineering Tower
Irvine, CA 92697-2575
United States

Gabrielle E. McGahey

University of California, Irvine - Department of Biomedical Engineering

3120 Natural Sciences II
Irvine, CA 92697-2715
United States

Albert F. Yee

University of California, Irvine - Department of Chemical Engineering and Materials Science

916 Engineering Tower
Irvine, CA 92697-2575
United States

University of California, Irvine - Department of Biomedical Engineering

3120 Natural Sciences II
Irvine, CA 92697-2715
United States

Michelle A. Digman (Contact Author)

University of California, Irvine - Department of Chemical Engineering and Materials Science ( email )

916 Engineering Tower
Irvine, CA 92697-2575
United States

University of California, Irvine - Department of Biomedical Engineering

3120 Natural Sciences II
Irvine, CA 92697-2715
United States

University of California, Irvine - Laboratory for Fluorescence Dynamics (LFD)

3208 Natural Sciences II
Irvine, CA 92697‑2715
United States

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