S.SM01.05.01 Mechanobiological Markers for Cancer Metastasis
Finding a cure against cancer progression has been a compelling argument in recent times. GLOBOCAN 2018 estimate suggests that around 9.6 million cancer deaths worldwide occur each year. Amidst the current challenges in cancer research, figuring new biological markers for metastatic cancers is a major challenge. Advanced cancers in the breast and prostate tend to metastasize (travel to a distant location from the initial site and cause a secondary tumor) and move into the bone marrow making it terminal. The work presented by Dr. Dinesh Katti, from North Dakota State University discusses a novel in vitro tissue-engineered bio-mimetic scaffold to model breast and prostate cancers. And this way, the research team suggests that this scaffold would suffice as a mechanobiological measure for evaluating the disease progression.
First up the research group developed ‘in vitro test beds’ which mimic biocompatible conditions and suitable microenvironment as that of cancer at the bone site. This is possible with the help of tissue-engineered polymeric scaffolds which are complexed with polymer clay nanocomposites that enable biocompatible, cell proliferative, and adequate mechanical properties for biomimetic activity. The incorporation of long-chained amino acids and nano-sized clays into the polymer composite yielded higher biocompatible and mechanical properties respectively. So, the bio-mimetic bone could now house the mesenchymal stem cells and provide a niche for them to differentiate into other cell types. Then, the mesenchymal stem cells seeded onto the bone-mimetic scaffold grow along with prostate or breast cancer cells to differentiate into dense tumoroids which mimic the in vivo metastatic cancers.
Nanoindentation experiments were performed to learn the nanomechanical properties of the cancer cells at the bone scaffold (mimics the metastatic site). They deliberate that the tumoroid cells had a significantly lower load-displacement response than prostate cancer cells. The group also shows that the elastic modulus gradually decreases in the cells from tumoroids as cancer progresses. So, from the initial experiments, we can understand that the cell's mechanical properties play a differential role between metastatic cells or cancer cells. So, cytoskeletal dynamics were explored via in vitro experiments. Immunofluorescence imaging of F-actin and alpha-tubulin, two significant cytoskeletal markers were analyzed. And it was shown that while prostate cancer cells had the F-actin spread throughout the cytosol, metastatic tumoroid cells had the F-actin populate at only the cell boundaries. The volume of actin/cell is significantly lower in tumoroid cells than prostate cells, whereas there was an insignificant tubulin change between the cells. This could explain the cells becoming soft(or losing cytoskeletal content) to undergo EMT transition at the metastatic site. Similar data of actin levels were seen in low migratory type breast cancer MCF-7 cells, but high migratory MDA-MB-231 cells did not follow the data.
This helps the group conclude that the low migratory type cancer cells form tight junctions at the bone site(in which actin plays a major part) reducing the mechanical properties of the cells, while high migratory cancer cell types form loose clusters showing less change in mechanical properties of the cells. So, this research work could potentially be a mechanobiological marker for learning the progression of cancer metastasis.