Delineating breast cancer cell interactions with engineered bone microenvironments

Authors

  • Anna V Taubenberger,

    1. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia
    2. Australian Prostate Cancer Research Centre Queensland, Brisbane, Australia
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    • The first two authors contributed equally to this work.
  • Verena M Quent,

    1. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia
    2. Department of Obstetrics and Gynecology, University Hospital Erlangen, Erlangen, Germany
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    • The first two authors contributed equally to this work.
  • Laure Thibaudeau,

    1. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia
    2. Australian Prostate Cancer Research Centre Queensland, Brisbane, Australia
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  • Judith A Clements,

    1. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia
    2. Australian Prostate Cancer Research Centre Queensland, Brisbane, Australia
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  • Dietmar W Hutmacher PhD

    Corresponding author
    1. Australian Prostate Cancer Research Centre Queensland, Brisbane, Australia
    2. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
    • Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Australia
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Address correspondence to: Dietmar W Hutmacher, Institute of Health and Biomedical Innovation, Queensland University of Technology, 60 Musk Avenue, 4059 Kelvin Grove, Queensland, Australia. E-mail: dietmar.hutmacher@qut.edu.au

Abstract

The mechanisms leading to colonization of metastatic breast cancer cells (BCa) in the skeleton are still not fully understood. Here, we demonstrate that mineralized extracellular matrices secreted by primary human osteoblasts (hOBM) modulate cellular processes associated with BCa colonization of bone. A panel of four BCa cell lines of different bone-metastatic potential (T47D, SUM1315, MDA-MB-231, and the bone-seeking subline MDA-MB-231BO) was cultured on hOBM. After 3 days, the metastatic BCa cells had undergone morphological changes on hOBM and were aligned along the hOBM's collagen type I fibrils that were decorated with bone-specific proteins. In contrast, nonmetastatic BCa cells showed a random orientation on hOBM. Atomic force microscopy-based single-cell force spectroscopy revealed that the metastatic cell lines adhered more strongly to hOBM compared with nonmetastatic cells. Function-blocking experiments indicated that β1-integrins mediated cell adhesion to hOBM. In addition, metastatic BCa cells migrated directionally and invaded hOBM, which was accompanied by enhanced MMP-2 and -9 secretion. Furthermore, we observed gene expression changes associated with osteomimickry in BCa cultured on hOBM. As such, osteopontin mRNA levels were significantly increased in SUM1315 and MDA-MB-231BO cells in a β1-integrin–dependent manner after growing for 3 days on hOBM compared with tissue culture plastic. In conclusion, our results show that extracellular matrices derived from human osteoblasts represent a powerful experimental platform to dissect mechanisms underlying critical steps in the development of bone metastases.

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