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Mechanical Properties of the Tumor Stromal Microenvironment Probed In Vitro and Ex Vivo by In Situ-Calibrated Optical Trap-Based Active Microrheology

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Abstract

One of the hallmarks of the malignant transformation of epithelial tissue is the modulation of stromal components of the microenvironment. In particular, aberrant extracellular matrix (ECM) remodeling and stiffening enhances tumor growth and survival and promotes metastasis. Type I collagen is one of the major ECM components. It serves as a scaffold protein in the stroma contributing to the tissue’s mechanical properties, imparting tensile strength and rigidity to tissues such as those of the skin, tendons, and lungs. Here we investigate the effects of intrinsic spatial heterogeneities due to fibrillar architecture, pore size and ligand density on the microscale and bulk mechanical properties of the ECM. Type I collagen hydrogels with topologies tuned by polymerization temperature and concentration to mimic physico-chemical properties of a normal tissue and tumor microenvironment were measured by in situ-calibrated Active Microrheology by Optical Trapping revealing significantly different microscale complex shear moduli at Hz-kHz frequencies and two orders of magnitude of strain amplitude that we compared to data from bulk rheology measurements. Access to higher frequencies enabled observation of transitions from elastic to viscous behavior that occur at ~200–2750 Hz, which largely was dependent on tissue architecture well outside the dynamic range of instrument acquisition possible with SAOS bulk rheology. We determined that mouse melanoma tumors and human breast tumors displayed complex moduli ~5–1000 Pa, increasing with frequency and displaying a nonlinear stress–strain response. Thus, we show the feasibility of a mechanical biopsy in efforts to provide a diagnostic tool to aid in the design of therapeutics complementary to those based on standard histopathology.

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Acknowledgments

This effort was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute. We thank Ben Blehm for helpful technical discussions and George Leiman for critical reading of the manuscript. We also thank Daniel Blair, and Xinran Zhang of Georgetown University for assistance with bulk rheometry.

Conflict of interest

Dr. Tanner and Alexus Devine have an international stage PCT application pending. Jack R Staunton, Wilfred Vieira, King Leung Fung and Ross Lake, all declare that they have no conflict of interest.

Ethical Statements

Animal studies were conducted under protocols approved by the National Cancer Institute, and the National Institutes of Health Animal Care and Use Committee. No human subjects research was performed in this studies.

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Authors and Affiliations

  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute (NIH), Bethesda, MD, 20892, USA

    Jack R. Staunton, Wilfred Vieira, King Leung Fung, Alexus Devine & Kandice Tanner

  2. Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute (NIH), Bethesda, MD, 20892, USA

    Ross Lake

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  1. Jack R. Staunton
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Correspondence to Kandice Tanner.

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Associate Editor Michael R. King oversaw the review of this article.

Kandice Tanner received her doctoral degree in Physics at the University of Illinois, Urbana-Champaign under Professor Enrico Gratton. She completed post-doctoral training at the University of California, Irvine specializing in dynamic imaging of thick tissues. She then became a Department of Defense Breast Cancer Post-doctoral fellow jointly at University of California, Berkeley and Lawrence Berkeley National Laboratory under Dr. Mina J. Bissell. Dr. Tanner joined the National Cancer Institute as a Stadtman Tenure-Track Investigator in July, 2012, where she integrates concepts from molecular biophysics and cell biology to learn how cells and tissues sense and respond to their physical microenvironment, and to thereby design therapeutics and cellular biotechnology. For her work, she has been awarded the 2013 National Cancer Institute Director’s Intramural Innovation Award, the 2015 NCI Leading Diversity award and the 2016 Young Fluorescence Investigator award from the Biophysical Society, She currently serves on the Membership Committee of the American Society of Cell Biology, the Minority Affairs Committee of the Biophysical Society and is a Member at large for the Division of Biological Physics of the American Physical Society.

This article is part of the 2016 Young Innovators Issue.

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Staunton, J.R., Vieira, W., Fung, K.L. et al. Mechanical Properties of the Tumor Stromal Microenvironment Probed In Vitro and Ex Vivo by In Situ-Calibrated Optical Trap-Based Active Microrheology. Cel. Mol. Bioeng. 9, 398–417 (2016). https://doi.org/10.1007/s12195-016-0460-9

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