UC Santa Cruz

Cancer remains a chief health concern across the developed world. With the expansion of life extending technologies, the aging population is set only to increase drastically in the coming years. As a result, novel modes of treating and identifying cancer early in its development is a goal held by researchers across the globe. This thesis focuses on one of the most common oncogenes and cancer drivers, Kirsten rat sarcoma virus oncogene, also known as KRAS. KRAS is a small GTPase responsible for relaying proliferative, differentiation and cell survival signals to the cell. Mutations in the RAS family of GTPases are present in almost a third of all cancers and are frequently overrepresented in lung and pancreatic cancers. However, RAS driven cancers have only until very recently been able to treated with single molecule inhibitors. Furthermore, not much is known about how the KRAS signaling pathway may interact with other established cellular pathways to remodel the transcriptome, an area that remains largely uninvestigated. Resolving these interconnected relationships holds much promise for the development of combinatorial therapies targeting these pathways as well as unlocking the potential for the identification of novel biomarkers. Here we aim to understand how KRAS signaling may coordinate with the hypoxia response pathway to induce a cellular phenotype similar to that of a stem cell, i.e., a cancer stem cell, as it is widely believed that such phenotypes confer a survival advantage. We also investigate the modes in which KRAS (G12C) signaling tunes the non-coding transcriptome and how this may be exploited for the development of novel biomarkers. Our findings indicate an inconclusive relationship between hypoxia gene signatures and “stemness,” a gene signature score as determined by a machine learning algorithm. We also find that KRAS (G12C) signaling tightly regulates the expression of key transposable elements (TEs) known as Alus, and that these TE’s may serve as suitable biomarkers. Taken together, our findings challenge conventional dogma regarding the formation of cancer stem cells and reveal novel interconnected relationships between KRAS signaling and TE regulation and expression.