INTEGRATION OF REDOX-REGULATED SIGNALING AND METABOLISM IN HEAD AND NECK CANCER

Head and Neck Squamous Cell Carcinoma (HNSCC) is a complex disease characterized by genetic and metabolic changes. Radiation therapy alone or combined with systemic chemotherapy is widely used for treatment of HNSCC as definitive treatment or as adjuvant treatment after surgery. Resistance to radiation therapy significantly impacts the ability to achieve local and regional remission to ultimately cure cancer. The disease heterogeneity, invasiveness and resistance to radiation constitute significant roadblocks for treatment and patients’ quality of life despite improvements in treatment modality over the last two decades and the emergence of new therapies. The research presented in this dissertation focuses on better understanding the underlying molecular mechanisms that elicit resistance to radiation treatment and drug-targeted therapy in HNSCC. To systematically study the molecular mechanisms contributing to radiation resistance, we developed a matched model of radiation resistance (SCC-61/rSCC-61 system) in HNSCC. We initially characterized differences between SCC-61 and rSCC-61 using quantitative mass spectrometry and complementary validation assays. We identified broad changes in signaling and metabolic pathways indicating mesenchymal-to-epithelial transition, increased DNA repair, and increased expression of antioxidant proteins (e.g. PRX, GSTpi). To further integrate signaling and metabolism in HNSCC, we developed a constraint-based computational model (COSMro) which combines multiple ‘omics’ (i.e. proteomics, redox proteomics, metabolomics, lipidomics) data and takes into consideration the relationships among signaling proteins, metabolic flux distribution, and the thermodynamic and stoichiometric characteristics of metabolites in the network. The application of COSMro to the matched model of radiation resistance demonstrates that multiple signaling and metabolic pathways converge to produce the radiation resistance phenotype. The findings highlight potential radiation resistance signatures including (1) decreased ROS and cholesterol levels, (2) increased flux through pentose phosphate pathway for increased production of NADPH, ribonucleotides and endogenous fatty acids, and (3) increased glutathione production, which together with increased NADPH and increased expression of ROS metabolizing enzymes, maintain decreased ROS and coordinate redox regulation of signaling and metabolic pathways. The rSCC-61/SCC-61 system provides opportunity for future investigations of redox-regulated mechanisms of response to radiation and drug-targeted therapy with potential for translation to clinic.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2017

Author dc:creator

• Moore, Jade T.

• computational modeling

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/82177

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/82177