Investigating One-Carbon Metabolic Alterations to Target Pancreatic Cancer Cachexia
Abstract
Pancreatic ductal adenocarcinoma (PDAC) -- the fiscal year 2022 Pancreatic Cancer Research Program (FY22 PCARP) Focus Area for this proposal -- is the third-leading cause of cancer-related deaths in the United States. Despite increased efforts for a couple of decades, the 5% survival rate for PDAC patients remains dismal. Up to 80% of advanced PDAC cases exhibit cancer cachexia. Cachectic patients display anorexia, attenuated adipose, and skeletal muscle mass, and hence less tolerance to chemotherapies and radiation treatments. Often, cancer patients that exhibit 30% loss of their body weight display up to 75% loss of skeletal muscle proteins, resulting in an irreversible functional impairment and significantly poor quality of life. Studies have shown that nutrition-based approaches alone have a limited efficacy in reversing the cachectic phenotype. The failure of these approaches is, at least in part, due to the fact that tumor cells also need common nutrients (such as essential amino acids and vitamins) for their unregulated growth. In fact, tumor cells vigorously devour circulating nutrients supplemented to these patients. Pancreatic tumors are under nutrient constraints and favor the metabolic pathways that support the tumor growth demands. Whether these metabolic adaptations by tumor cells have systemic consequences, such as cancer cachexia, remains to be explored. Thus, the main rationale of our project is driven by the gaps in our understanding of the systemic effects of tumor metabolism that drive cancer cachexia in pancreatic cancer patients. The pancreatic tumor microenvironment is dense and presents significant nutritional constraints. Our data show that pancreatic tumor cells upregulate 1 carbon (1C) metabolism under glucose limitation in conditions mimicking the tumor microenvironment. The 1C pathway supports the production of building blocks needed for the growth of tumor cells and requires vitamins including vitamin B6 (helps in three steps of 1C cycle pathway) for the maintenance of the pathway. Of note, vitamin B6 (VB6), is also very important for the proper functioning of the immune system. Studies have shown depleted circulating VB6 levels in PDAC patients. In our preliminary data, we also observed decreased circulating VB6 levels in PDAC patients and tumor-bearing mice compared to non-cancer patients or the respective healthy mice controls. We noted increased pancreatic tumor cell growth upon VB6 addition to the culture medium and tumor cell growth dependency on VB6. More importantly, VB6 is also critical for muscle biology. An earlier study showed that deregulation of the transsulfuration pathway in muscle leads to muscle cell breakdown, also called muscle atrophy. VB6 is critically required for the transsulfuration pathway, and its absence leads to the buildup of byproducts in muscle, causing muscle damage. We thus hypothesize that, under nutritional constraints, the tumor cell metabolically adapts and upregulates the mechanisms that cause systemic imbalances of VB6 in the tumor-bearing host. This systemic (blood) depletion of VB6 triggers muscle damage and induces cancer cachexia in pancreatic cancer patients. Based on our data with myeloid-derived suppressor cells (MDSCs), we further hypothesize that VB6 supplementation can, in parallel, reprogram the immune cells in skeletal muscles to diminish muscle wasting. Thus, our study has a direct impact on the FY22 PCARP Focus Area Understanding the relationship between metabolic disruptions in pancreatic cancer and their systemic effects, including diabetes and cachexia. To date, only few studies have shown the impact of vitamins (vitamin D) on muscle biology. The role of VB6 in muscle weight loss and cancer cachexia has not been investigated so far. Hence, the proposed study on understanding the critical role of VB6 limitation on muscle loss in pancreatic cancer patients is highly innovative. Given the exploratory nature of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311001
Entities
People
- Kamiya Mehla
Organizations
- United States Army
- University of Oklahoma Health Sciences Center