The Roles of NF-kB, Activin, and Sphingosine-1-Phosphate in Promoting Non-Small Cell Lung Cancer-Initiating Cell Phenotypes
Wamsley, James, Biochemistry and Molecular Genetics - Graduate School of Arts and Sciences, University of Virginia
Mayo, Marty, Department of Biochemistry and Molecular Genetics, University of Virginia
Despite recent advances in personalized therapies, non-small cell lung cancer (NSCLC) remains the most deadly malignancy in the Western world. The frequency of metastases and acquired drug resistance contribute to the high rates of mortality. An evolutionarily conserved cellular program termed the epithelial-to-mesenchymal transition (EMT) promotes metastasis and drug resistance by enriching for a pool of cancer-initiating cells (CICs). The migratory and invasive characteristics of CICs initiate the metastatic cascade. CICs also aid in the final step of metastasis, colonization, through their ability to self-renew and generate progenitor cells that comprise macrometastases. This pool of cells is also highly insensitive to both traditional and targeted treatments, enabling it to regenerate carcinoma cells within the primary tumor that undergo apoptosis due to drug treatment. Work presented in this dissertation illustrates that treatment of three-dimensional (3D) spheroid NSCLC cultures stimulated with tumor necrosis factor (TNF) and transforming growth factor-beta (TGFβ) induces nuclear factor-kappa B (NF-κB) to promote EMT and the subsequent formation of CICs. Furthermore, NF-κB upregulates Activin, a TGFβ superfamily member, to sustain the mesenchymal phenotype over a four-day time course. Preliminary data also links the bioactive signaling lipid, sphingosine-1-phosphate (S1P), to EMT within NSCLC. Since successful treatment of NSCLC theoretically requires eradication of this pool of self-renewing cells, soluble factors that promote CIC phenotypes are excellent candidates for targeted therapeutic intervention.
PHD (Doctor of Philosophy)
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