Access Type

Open Access Dissertation

Date of Award

January 2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Henry H. Heng

Abstract

The central paradox associated with current cancer therapeutic strategies is initially effective treatment, which eliminates a high tumor cell count, consistently results in successful drug resistance. Mathematical and evolutionary modeling have previously suggested that therapeutic intervention could provide selective pressure for the expansion of resistant variants. Drug-related stress has been associated with genome chaos, a common phenomenon in cancer characterized as rapid, stochastic genomic fragmentation and reorganization. Since cancer represents an evolutionary process, analysis within the context of genome-mediated cancer evolution can shed light on this key problem of therapeutics. We propose that genomic change is a general response to therapeutics. Drug-induced karyotypic alteration has been linked with transcriptomic elevation, implying that drug-induced genomic change would paradoxically provide an advantage for cancer cells through an increase of genome heterogeneity or evolutionary potential for selection. In vivo and in vitro models were tested using different therapeutic approaches, and surviving cells displayed altered karyotypes for each case. To determine whether drug-induced genome change could provide a long-term advantage to cancer cell survival, a karyotypically stable colon cancer cell line was treated with chemotherapy, and growth patterns were followed in a series of in vitro single-cell and population-based experiments. Outlier treated cells displayed faster growth rates than untreated cells, and population-based data support that these outliers may drive cancer progression post-therapy. This macro-evolutionary based, general mechanism of cancer drug resistance challenges the current therapeutic aim of maximizing cancer cell death and has great implications in the development and administration of future therapeutic strategies.

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