Biology subjects

Holen, I.

Publications and source records attributed to Holen, I..

3 recordsLinked to original sources

bioRxiv2021

Atomic force microscopy reveals the mechanical properties of breast cancer bone metastases

Mechanically dependent processes are essential in cancer metastases. However, reliable mechanical characterisation of metastatic cancer remains challenging whilst maintaining the tissue complexity and an intact sample. Using atomic force microscopy, we quantified the micro-mechanical properties of relatively intact metastatic breast tumours and their surrounding bone microenvironment isolated from mice, and compared with other breast cancer models both ex vivo and in vitro. A unique mechanical distribution of extremely low elastic modulus and viscosity was identified on metastatic tumours, which were significantly more compliant than both 2D in vitro cultured cancer cells and subcutaneous tumour explants. The presence of mechanically distinct metastatic tumour did not result in alterations of the mechanical properties of the surrounding microenvironment at meso-scale distances (> 200 {micro}m). These findings demonstrate the utility of atomic force microscopy in studies of complex tissues and provide new insights into the mechanical properties of cancer metastases in bone.

cancer biology↗

bioRxiv2020

Mechanical Heterogeneity in the Bone Microenvironment as Characterised by Atomic Force Microscopy

Bones are structurally heterogeneous organs with diverse functions that undergo mechanical stimuli across multiple length scales. Mechanical characterisation of the bone microenvironment is important for understanding how bones function in health and disease. Here we describe the mechanical architecture of cortical bone, the growth plate, metaphysis and marrow in fresh murine bones, probed using atomic force microscopy in physiological buffer. Both elastic and viscoelastic properties are found to be highly heterogeneous with moduli ranging over 3 to 5 orders of magnitude, both within and across regions. All regions include extremely soft areas, with moduli of a few Pascal and viscosities as low as tens Pa*s. Aging impacts the viscoelasticity of the bone marrow strongly but has limited effect on the other regions studied. Our approach provides the opportunity to explore the mechanical properties of complex tissues at the length scale relevant to cellular processes and how these impact on aging and disease. SIGNIFICANCEThe mechanical properties of biological materials at cellular scale are involved in guiding cell fate. However, there is a critical gap in our knowledge of such properties in complex tissues. The physiochemical environment surrounding the cells in in-vitro studies differs significantly from that found in vivo. Existing mechanical characterisation of real tissues are largely limited to properties at larger scales, structurally simple (e.g. epithelial monolayers) or non-intact (e.g. through fixation) tissues. In this paper, we address this critical gap and present the micro-mechanical properties of the relatively intact bone microenvironment. The measured Youngs moduli and viscosity provide a sound guidance in bioengineering designs. The striking heterogeneity at supracellular scale reveals the potential contribution of the mechanical properties in guiding cell behaviour.

biophysics↗

bioRxiv2019

RUNX/CBFβ transcription factor complexes promote the phenotypic plasticity of metastatic breast cancer cells

Epithelial to mesenchymal transition (EMT) is a dynamic process that drives cancer cell plasticity and is thought to play a major role in metastasis. Here we show that the plasticity of metastatic breast cancer cells can be promoted by the activity of the RUNX transcription factors. We demonstrate that the RUNX co-regulator CBF{beta} is essential to maintain the mesenchymal phenotype of triple-negative breast cancer cells and that CBF{beta}-depleted cells undergo a mesenchymal to epithelial transition (MET) and re-organise into acini-like structures, reminiscent of those formed by epithelial breast cells. We subsequently show, using an inducible CBF{beta} system, that the MET can be reversed, thus demonstrating the plasticity of RUNX/CBF{beta}-mediated EMT. Moreover, the MET can be reversed by expression of the EMT transcription factor Slug whose expression is dependent on CBF{beta}, RUNX1 and RUNX2. Finally, we demonstrate that loss of CBF{beta} inhibits the ability of metastatic breast cancer cells to invade bone cell cultures and suppresses their ability to form bone metastases in vivo. Together our findings demonstrate that the RUNX/CBF{beta} complexes can determine the plasticity of the metastatic cancer cell phenotypes, suggesting that their regulation in different micro-environments may play a key role in the establishment of metastatic tumours.

cancer biology↗