This project is led by the Johns Hopkins University School of Medicine
This project examines the mechanisms of stress-induced phenotypic changes in cell and chromatin structure that play a critical role in evolution.
The ability of cancer cells to develop resistance to chemotherapy agents is a fundamental property of cancer and one of the leading eventual causes of death. Nuclear structure is often altered in cancer due to spatial rearrangements of chromatin organization by activation of oncogenes and other chromatin remodeling genes. We look at how these processes are perturbed in the development and control of the therapeutic resistance in cancer.
We use prostate cancer cell lines, PC-3 and DU-145 along with counterparts of these lines that are resistant to taxol (paclitaxel) resulting in an approximately 40-fold decreased sensitivity to the drug. These cell lines are identical to the parent lines with the only difference being resistance to chemotherapeutic agents. These cells provide us with an opportunity to examine the evolutionary impact of resistance development on the cell’s responses to stress, and on nuclear structure and DNA organization.
A central theme of this project is a generalized “mechanical” analysis of the phenotype of cancer in cells and how mechanical forces transmit signals to the cell. Using paclitaxel resistant cells in comparison to parent lines, we examine the connection between changes in the cytoskeleton and resulting modifications to DNA organization and transcriptional activity. Our research includes examining the difference in nuclear matrix protein composition, differences in response to micro-environmental stresses, differences in nuclear morphometry, and changes in glycosylation patterns of the nuclear structural proteins.