Sunday, May 5, 2024
5/5/2024
Project Summary/Abstract I am an MD/PhD student in the laboratory of Dr. Susanne Wells at Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine. This proposal outlines a research project designed to prepare me for a combined dual-degree career path in metabolism and cancer biology. The overall research goal is to determine how loss of the Fanconi Anemia (FA) DNA repair pathway leads to metabolic reprogramming and tumor progression. Inherited loss-of-function mutations in the FA pathway promote the development of uniquely aggressive head and neck squamous cell carcinoma (HNSCC) progression and a poor prognosis. While up to 20% of sporadic HNSCC tumors harbor mutations in FA genes, it is unclear whether sporadic loss of the FA pathway also promotes aggressive tumor progression. To begin to answer this question, I have generated an in vivo xenograft model wherein FA-deficient knockdown (vs. –proficient control) sporadic HNSCC cells were injected into the cheek mucosa of immunodeficient mice. FA-deficient tumors were more proliferative, invasive, and of higher grade than their FA-proficient counterparts. Previous in vitro studies in the Wells laboratory identified a potential mechanism for these phenotypes by discovering two drivers of invasion in FA-deficient HNSCC cells: (1) activation of the non-homologous end joining associated DNA-dependent protein kinase (DNA- PK) and dependent downstream stimulation of the GTPase Rac1, and (2) accumulation of the glycosphingolipid GM3 ganglioside. Rac1 activation can upregulate folate and potentially related metabolic pathways like 1-carbon (1C) metabolism. In turn, 1C metabolism can contribute to GM3 ganglioside synthesis and other cancer-driving processes. My experiments have determined that 1C metabolism was indeed upregulated across multiple FA- deficient HNSCC cell lines, and the incorporation of 1C inhibitors sensitized FA-deficient HNSCC cells and tumor spheroids to decreased growth compared to FA-proficient counterparts. Thus, FA pathway loss-dependent activation of DNA-PK and Rac1 may stimulate 1C metabolism, and 1C metabolism in turn may drive aggressive tumor behavior in FA-deficient systems. Aim 1 will test whether DNA-PK/Rac1 activation are FA-dependent stimulators of 1C metabolism. I expect to detect activation of DNA-PK/Rac1 and dependent upregulation of 1C metabolites across multiple 2D and 3D tumor spheroids and organotypic raft models of FA-deficient HNSCC cells. These experiments will therefore define a novel mechanism by which loss of a DNA repair pathway promotes aberrant metabolic stimulation. Aim 2 will define the functional roles of 1C metabolism in FA disease phenotypes by testing enzymes and metabolites as candidate therapeutic targets. I expect that inhibitors of 1C metabolism will suppress cancer phenotypes such as migration and invasion in vitro, and prevent the growth and progression of FA-deficient HNSCC tumors in vivo. Taken together, these experiments will define novel links between FA pathway loss and cancer metabolism, and thus explore possible metabolic or nutritional interventions for the prevention and/or treatment of lethal cancers in FA and in the general population.
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