Mechanical Architecture in the Context of Intact Complex Tissue — A Case Study of the Breast Cancer Metastasis to Bone

Session

Stream 4 (AFM): Quantitative SPM for Biology, Biomedicine, and Bioinspired Technologies

Authors

Xinyue Chen (2), Russell Hughes (1), Nic Mullin (2), Rhoda Hawkins (2), Ingunn Holen (1), Nicola Brown (1), Jamie Hobbs (2)

Affiliations

1. Department of Oncology and Metabolism, University of Sheffield
2. Department of Physics and Astronomy, University of Sheffield

Keywords

AFM, viscoelasticity, cancer models, bone microenvironment

Abstract text

We introduce an improved platform based on atomic force microscopy (AFM) to quantify the micro-mechanical properties, including both elastic moduli and viscosity, of relatively intact metastatic breast tumour in bone. A unique mechanical distribution of extremely high deformability (Young’s modulus down to a few Pa) and low viscosity (viscosity down to a few Pa×s) was identified, which is significantly more compliant (> 10 times) than the mechanical properties found using in-vitro systems (e.g. cancer cells on a petri-dish) both by ourselves and others. These findings shed light on how mechanics plays a deterministic role in cancer development and metastasis, as well as spotlight the gap between in-vitro models and real tissues in studies of mechanobiology.

 

Bone metastases of breast cancer (metastatic tumours, MT) were established using GFP expressed MDA-MB-231 cells based on a mouse model [1]. Point force (F) vs. indentation (δ) and creep measurements by colloidal probe AFM [2] were applied at randomly selected positions within the MT area contained by the fresh (un-fixed) murine bones in physiological buffer, aided by the in-situ fluorescent imaging. The weighted Sneddon model and Kelvin-Voigt model were employed to obtain the Young’s moduli and viscosity from the AFM data. Such mechanical characterisations were also applied on the 2D in-vitro model (MDA-MB-231 cells on petri-dish), the explanted subcutaneous tumour (SCT) and the metaphysis of bones (BM) from mice with or without tumours.

 

The resultant mechanical properties of the 2D models are over an order of magnitude higher than those of tumours, indicating the importance of a proper 3D environment and acellular components in cancer mechanics. The MT is considerably more compliant than the SCT, suggesting other mechanical cues in addition to 3D environment contribute to bone metastases of breast cancer. Meanwhile, the MT was found to be mechanically distinct from its surrounding environment (i.e. the BM) and it did not mechanically alter the environment at meso-scale distance (> 200 µm). These findings could inspire the design of more realistic in-vitro cancer research models or mechanical interventions as anti-cancer drugs/treatments. This improved AFM based system is powerful for further characterisations of bones containing tumour in the presence of anti-cancer therapy or other complex tissues.

References

[1] P.D. Ottewell, et al. (2014) Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo, Clin Cancer Res, 20: 2922-2932. 

[2] X. Chen, et al. (2020) Mechanical Heterogeneity in the Bone Microenvironment as Characterised by Atomic Force Microscopy, Biophys. J., 119(3): 502-513.