Investigating the Biophysics of Giant Polyploidal Cancer Cells in an Aging Tumor Stroma

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Generally it is assumed that senescence, or cell aging and death, is a good thing when it comes to tumor growth -- as cells that are deteriorating and die will not continue to grow and proliferate. However, it has been found that if senescent connective tissue cells (stromal cells) accumulate in premalignant tissue, they can actually alter the tissue microenvironment and promote cancer development. This project will investigate how breast cancer cells react to the changes in the extracellular mechanical environment that occurs with the accumulation of senescent stromal cells. In particular, giant polyploidal cancer cells, which have been observed to develop more frequently in the presence of senescent stromal cells and are highly invasive and resistant to chemo therapy, will be studied to determine how this environmental change influences their development. In addition to the impact that improved understanding of how these invasive, treatment-resistant cells develop will have, the research team will organize outreach activities that include presentations at local schools, development of course materials for the Brown Science Prep program, and the development of an animated, science-based cartoon that describes cancer biomechanics.This project will investigate the single cell biophysical profile of breast cancer cells before and after exposure to conditioned media from senescent stromal cells. In particular, a high-content mechanomic screening approach will be used to profile: the forces exerted by cells on the extracellular matrix; cytoskeletal and nuclear mechanics; morphology, motility, and adhesion. This will be done for treated and untreated breast cancer cells as well as giant polyploidal cancer cells. By looking at changes in intracellular mechanics, cell and nuclear morphology, traction force generation, and motility, it may be possible to develop new strategies to target giant polyploidal cancer cells. In addition, as it is hypothesized that solid stress from the surrounding tissue contributes to a-mitotic budding seen in giant polyploidal cancer cells, a model will be developed to test the hypothesis.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.