Cancer is known for its unregulated and mutagenic characteristics. The topic of targeting cancer by inhibiting the metabolic pathways it uses to thrive has been a focus of modern cancer research. Specifically, in lung cancer, the transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a focus. This transformation often comes with a grimmer prognosis and reduced survival rate. This is primarily due to SCLC being resistant to epidermal growth factor receptor (EGFR) inhibitors. This frontline treatment for EGFR mutant NSCLC has shown to be quite effective until transformation to SCLC occurs. To further study the metabolic factors responsible for this transformation, a metabolic screening was conducted on SCLC transformed lung tissues and tumor adjacent normal lung tissues. This analysis revealed that the amino acid L-arginine and intermediates in its biosynthetic pathway were severely dysregulated. While L-arginine supplementation has shown to inhibit the growth of breast and colorectal cancers, there is little literature about its effects on lung cancer. Using cell viability and gene expression screening tools, we have identified arginine metabolizing genes ARG2, GATM, and OAT as being upregulated in NSCLC treated with high concentrations of an EGFR inhibitor. These high treatments also correlate with increased expression of neuronal differentiation factor 1 (NEUROD1), which has been shown to drive tumorigenesis, metastasis, and SCLC transformation. These findings show a role for altering arginine metabolism to accomplish drug resistance through SCLC transformation. These findings will hopefully pave the way for later clinical use of arginine converting enzymes and NEUROD1 expression levels as predictive markers of early drug resistance and SCLC transformation.

<p dir="ltr">The SWI/SNF chromatin remodeling complex plays a critical role in modulating DNA accessibility and consequently regulating downstream gene expression during development and disease. This dissertation focuses on comprehensively defining the functions of <i>Bicra</i>/GLTSCR1 in hematopoiesis and the role of SMARCC2 in neuroendocrine differentiation of prostate cancer. Our lab identified a novel GLTSCR1 containing BAF subcomplex; GBAF. To determine the unknown function of <i>Bicra</i>/GLTSCR1, we generated a CRISPR knockout mouse model for <i>Bicra</i>. Through a series of histological assays, flow cytometry assays, and genomic profiling we establish that <i>Bicra</i>/GLTSCR1 plays a critical role in red blood cell enucleation via central macrophages in fetal liver. In the latter half of the dissertation, I focus on prostate cancer. The treatment-emergent neuroendocrine prostate cancer (TE-NEPC) subtype is a highly aggressive disease state with limited curative strategies. While a few subunits of the SWI/SNF complex are known to be upregulated in TE-NEPC, the underlying biological mechanism remains unclear. The findings of this research establish a dynamic switch in the core structural SWI/SNF subunits upon neuroendocrine differentiation (NED). Furthermore, a phenotypic assay and RNA-seq analysis pinpoint the reduced neuroendocrine differentiation potential upon knockdown of SMARCC2. I also identify a novel alternatively spliced SMARCC2 isoform that is exclusively expressed upon NED and favors the formation of the Polybromo1 containing Brg1 associated factor (PBAF) subcomplex. Overall, I define a unique role for SWI/SNF complex subunits in cell fate and lineage commitment during normal hematopoiesis and malignant prostate cancer progression. Further elucidating the context-dependent function of the SWI/SNF complex may reveal new therapeutic opportunities in hematologic and prostate malignancies.</p>