Biology and Biomedical Sciences: Molecular Genetics and Genomics
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Robi D Mitra
In the last twenty years both computational biology and cancer biology have made great strides and in the last 5 years the merger of the two has helped to revolutionize our knowledge of personalized targeted therapy and the diversity of cancer. In cancer, cell-to-cell interactions between tumor cells and their microenvironment are critical determinants of tumor tissue biology and therapeutic responses. Interactions between glioblastoma (GBM) cells and endothelial cells (ECs) establish a purported stem cell niche. We hypothesized that genes that mediate these interactions would be important, particularly as therapeutic targets. Using a novel computational approach to deconvoluting expression data from mixed physical coculture of GBM cells and ECs, we identified a previously undescribed upregulation of the cAMP specific phosphodiesterase PDE7B in GBM cells in response to ECs. We further found that elevated PDE7B expression occurs in most GBM cases and has a negative effect on survival. PDE7B overexpression resulted in the expansion of a stem-like cell subpopulation, increased tumor aggressiveness, and increased growth in an intracranial GBM model. This deconvolution algorithm provides a new tool for cancer biology, particularly when looking at cell-to-cell interactions, and these results identify PDE7B as a therapeutic target in GBM.
Brooks, Michael, "Transcriptional Analysis of Reciprocal Tumor-Microenvironment Interactions in Glioblastoma" (2014). All Theses and Dissertations (ETDs). 1222.