Diagnosis of pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognostic outcome. While progress has been made in treatments of other cancer types, PDAC survivability has not increased in the last 80 years. In order to understand why this type of cancer is particularly difficult to treat, we must determine what contributes to its ability to survive stress and proliferate. Metabolic adaptations, and signaling events that control them, have been implicated in contributing to the capability of PDAC to adapt to stress associated with nutrient and oxygen deprivation at the tumor site and with chemotherapy administrations. Particularly, rewiring of NADPH production has been recently shown to play a key role in PDAC; yet, our understanding of NADPH metabolism and how it is rewired to support PDAC is still in its infancy. NADPH is recycled through reduction of NADP+ by several enzymatic systems in cells. However, de novo NADP+ is only synthesized by one known enzymatic reaction catalyzed by NAD+ kinase (NADK). This suggests that high NADK activity may constitute a vital mechanism of survival utilized by PDAC. Supporting this idea, a recent study shows that NADK supports KRAS induced tumorigenesis in PDAC and that silencing NADK leads to PDAC growth arrest. Here, I aim to determine what regulates the function of NADK and what cellular processes are altered in response to NADK silencing. My preliminary data shows that PKC can phosphorylate NADK and that in response to NADK depletion, serine synthesis enzymes decrease in expression. Thus, I hypothesize that oncogenic signaling triggers hyperactivation of NADK in PDAC, which results in increased NADP+ synthesis and favors metabolic reprogramming that supports increased flux through the serine synthesis pathway. My work can help us understand how PDAC develops its tumorigenic potential, and thus, can open up new avenues of treatment.
Pancreatic cancer is the fourth leading cause of death among all cancer types. Expected 5 year survival rate is about 5%, and while researchers have made great strides at understanding what genetic lesions initiate and support tumorigenesis, little to no progress has been made in diagnosing, preventing or curing pancreatic cancer. This project aims to understand what metabolic and redox pathways are essential to the progression of pancreatic cancer in order to provide alternative therapeutic options for treatment of this disease.
| Schild, Tanya; Low, Vivien; Blenis, John et al. (2018) Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization. Cancer Cell 33:347-354 |
