Advanced dynamic atomic force microscopy methods for high-resolution in vitro biomechanical assays of cancer cells

Human cell mechanical properties can change significantly due to invasion of foreign organisms or disease. For example, recent research has clearly shown that the mechanical properties (elasticity, adhesion) of tumor cells change dramatically when they are about to metastasize. Thus elasticity and adhesion measurements of a living cell can be used as indicators of its health or as early indicators of impending disease. Such biomechanical assays can also offer valuable insight into the underlying disease mechanisms and aid in the discovery of anti-cancer treatments that target the cytoskeleton of cancer cells. The proposed work deals with the development of advanced methods using the Atomic Force Microscope for fast, high resolution, minimally invasive, biomechanical assays of cancer cells. As opposed to many existing methods of cell biomechanical assays, the proposed methods will provide quantitative maps or distributions of mechanical properties of cancer cells. By finely resolving variations of local nanomechanical properties of living cancer cells a wealth of new diagnostic information on cancer biomechanics will become available. Such new information could be widely useful for early cancer diagnosis, anti-cancer drugs, and for a better fundamental understanding of cancer cell biophysics/biomechanics.

The proposed work will be of great significance to the AFM community particularly to those with interest in biological samples under liquid environments. This community consists of thousands of scientist's worldwide working in industries, Universities or research Laboratories. The work will also impact the large cancer biophysics/cancer biomechanics community worldwide. The plan to impact both these communities consists of (a) Technology transfer via industry outreach: The PI's have close connections to leading AFM industries and will use these connections for transferring the results of the proposed research directly to their AFM research divisions by means of talks and application notes. (b) Cyber-enabled dissemination via the nanoHUB: nanoHUB (www.nanohub.org) is the extremely successful web portal of the US National Science Foundation funded Network for Computational Nanotechnology. On nanoHUB, Raman's group has developed VEDA (Virtual environment for dynamic AFM) which is a very successful set of state-of-the-art simulation tools for dynamic AFM - it is used by more than 500 users from more than 20 countries who have run thousands of simulations. As a part of this project, many examples relevant to the proposed methods will be included in VEDA, especially a section that describes how VEDA can be used to convert observed material property contrast to quantitative mechanical property maps. This will allow the hundreds of VEDA users worldwide to simulate and understand the proposed methods for applications to biology in liquid environments. (c) Technical conferences and high impact journal papers: The PI's will present talks based on the proposed work at leading international conferences, thus engaging directly the AFM community. Based on their strong track record, if the research results are compelling, the PI's will also aim to publish the results in high-impact journals. (d) Transfer to the biomedical community will be ensured through collaborations within the Oxford Medical Physics Research Group (includes researchers from across Oxford university and the local NHS Medical Physics departments, in particular the Gray Institute for Radiation, Oncology and Biology, the Medical Physics Department at the Oxford Radcliffe NHS trust and the Oxford Centre for Functional MRI of the Brain), Green Templeton College and the James Martin 21st century School. Dissemination of the research results to a wide audience will also be possible though presentations at the Royal Society of Medicine. The results will be incorporated in teaching at Oxford Biochem. Dept., the new Masters programme at the JM School and the development of new courses of Biomedicine for Physicists.