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Mechanotaxis in the guidance of cancer metastasis

Final Activity Report Summary - MGCM (Mechanotaxis in the guidance of cancer metastasis)

Cancer is a collective term used to describe 100 different but related diseases. Cancer is one of the leading causes of morbidity and mortality worldwide. Recent advances in medical and biological sciences have rendered cancer mostly treatable at the primary site. Nonetheless, recurring morbidity and mortality are entirely attributed to metastasis. Therefore, research that targets the multiple facets of metastasis is vital to effectively cope with cancer in its entirety.

Cell migration is a key event in many physiological processes, such as embryogenesis, and pathological states, such as cancer metastasis. Migration of normal and malignant cells toward chemical stimuli is well established. Nonetheless, recent evidence suggests that the mechanical properties of the tissue microenvironment also dictate the fate of cells. In a malignant microenvironment, cancer cells have to encounter a particularly rigid microenvironment. It is thus of great importance to investigate whether the mechanical input from the primary tumour microenvironment first and the metastatic site next affects the metastatic potential of cancer cells.

The aim of the project was to investigate whether cancer cells are migrating toward mechanical cues of their microenvironment and how these cues may also affect other primary cell functions that are directly related to successful metastasis, including proliferation and evasion of apoptosis. Via this project, it was successfully shown that cells from a human fibrosarcoma cell line demonstrated higher motility, directional migration toward stiffer substrates, a response termed mechanotaxis, greater proliferation and traction force exertion, and lower death on substrates that mimicked the rigidity of connective tissue, which is where fibrosarcoma cells were derived from. Similarly, experiments with primary cells from a human osteosarcoma, which is one of the most prominent childhood cancers, showed that death is minimized and traction forces maximized at a substrate rigidity close to that where osteogenesis is first evidenced. These data demonstrate that cancer cells are not only functionally but also preferentially responsive to the rigidity of their substrate.

The next steps of the project include the identification of genes and proteins that are directly involved with mechanosensing. Our current results show that cancer cells (human primary and cell line cells) exposed to various substrate rigidities upregulate specific genes and gene groups as well as intracellular signalling cascades. Utilisation of state-of-the-art techniques, including gene silencing and high throughput proteomics assist us in further teasing out the precise role of the thus far identified genes and proteins in cancer cell mechanosensing and mechanotaxis.

Another successful aspect of the project was the integration of mathematical modelling, image analysis and high throughput data algorithms in the effort to exploit more information from our biological data. With national and international collaborations, we were able to develop a mathematical model to better understand the formation and maturation of focal adhesions, which are the physical cell mechanosensors. Furthermore, we have successfully developed algorithms to investigate the association of cell morphology to focal adhesion distribution and are currently in the process of testing novel algorithms for the management and extraction of information from the multitude of biological data deriving from gene arrays and high throughput proteomic analyses.

The findings of the MGCM project offers a comprehensive and multidisciplinary attempt to understand cancer cell mechanosensing, specifically as it pertains to metastasis. By understanding the impact of microenvironment mechanics on the successful metastasis of cancer cells, we will be able to better assess the predisposition of a tissue to become a metastatic site for a specific form of cancer and thus more effectively administer established or novel pharmacological agents.