Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Genetics and Genomics

Language

English (en)

Date of Award

Spring 1-6-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Robi D Mitra

Abstract

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.

Comments

Permanent URL: http://dx.doi.org/10.7936/K70K26KZ

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