Research in the Chapkin lab focuses on dietary/microbial modulators related to the prevention of cancer and chronic inflammatory diseases. NIH has continuously funded our program for the past 32 years. During this time, we have made highly significant contributions in cancer cell biology with specific emphasis in five foci: elucidation of signal transduction processes in intestinal stem cells; plasma membrane spatiotemporal dynamics, cancer biology and dietary membrane altering agents; investigation of the role of inflammation as a critical factor in cancer development, and its modulation by environmental/botanical agents; establishment of models for chronic inflammation and cancer prevention studies; and development of novel noninvasive Systems Biology-based methodologies to assess crosstalk between the gut microbiome and the host transcriptome and its application to translational research.
Noninvasive approach to monitor host/microbe interactions
Early detection can be considered a method for prevention in that it can ameliorate severe morbidity and mortality. Our team has identified novel noninvasive early detection biomarkers in feces containing exfoliated cells shed from the gut to address this need. We use these biomarkers to classify and predict host chronic inflammation, metabolism, immune status, and gut barrier function on a molecular level in mouse models, veterinary species, and humans. Mathematical models are used to determine dynamical system behavior to derive therapeutic strategies. Outcomes include the prediction of new cancer targets based on intracellular signaling pathways. Cutting edge applications include the influence of diet and gut microbes on host gene expression in neonates and adults, and analysis of gut microbe (prokaryotic) and host (eukaryotic) crosstalk.
J. W. Lampe, E. Kim, L. Levy, L. A. Davidson, J. S. Goldsby, F. L. Miles, S. L. Navarro, T. W. Randolph, N. Zhao, I. Ivanov, A. M. Kaz, C. Damman, D. M. Hockenbery, M. A. J. Hullar, R. S. Chapkin, Colonic mucosal and exfoliome transcriptomic profiling and fecal microbiome response to flaxseed lignan extract intervention in humans. Am. J. Clin. Nutr. 110, 377–390 (2019).
Diet and microbes as modifiers of stem cells and colon cancer
Projects in this research area are designed to assess how diet- and microbe-derived tryptophan metabolites mediate aryl hydrocarbon receptor (AhR)-dependent intestinal stem cell function. We are interrogating the effects of diet and microbe-derived AhR mediators on intestinal stem cell homeostasis and colon cancer using tissue and stem cell-specific AhR transgenic mice, and 3D-human colonic organoids since the transformation of adult stem cells is a crucial route towards initiating intestinal cancer. Our novel preliminary data supports this objective, indicating that microbe-derived AhR ligands have a direct effect on intestinal stem cells. Our results collectively provide a critical new paradigm in understanding the molecular mechanisms through which diet and gut microbes modulate colon cancer risk.
Y. Cheng, U. H. Jin, L. A. Davidson, R. S. Chapkin, A. Jayaraman, P. Tamamis, A. Orr, C. Allred, M. S. Denison, A. Soshilov, E. Weaver, S. Safe, Microbial-derived 1,4-Dihydroxy-2-naphthoic Acid and related compounds as aryl hydrocarbon receptor agonists/antagonists: Structure-activity relationships and receptor modeling. Toxicol. Sci. 155, 458–473 (2017).
Membrane therapy as a molecular basis for cancer prevention
Although cellular membranes are the environment in which many cancer-related mutated proteins function, it is now apparent that protein assemblies can be organized to form distinct micro- or nanodomains that facilitate signaling events. Interestingly, cell membrane composition is altered during human disease processes such as cancer and obesity. For example, an increased rate of cholesterol synthesis in cancerous tissues has long been recognized as an essential aspect of the rewired metabolism of transformed cells. However, the contribution of cholesterol to cellular function in disease models is not yet fully understood. Since diet is a significant modulator of cell membrane composition, we are examining scenarios in which nutrition-induced changes in plasma membrane composition impact cancer-causing mutated proteolipid interactions (nanoclustering) in Drosophila and transgenic mouse models.
M. L. Salinas, N. R. Fuentes, R. Choate, D. N. McMurray, R. S. Chapkin, AdipoRon attenuates Wnt signaling by reducing cholesterol-dependent membrane rigidity. Biophys. J. 118, 885–897 (2020).
Precision nutrition-targeted deletion of cancer stem cells
We are assessing how nutritional combinations of fish oil and fermentable fiber (pesco-vegetarian diet, PVD) uniquely reduce colon cancer risk in humans. This PVD effect is mediated, in part, by its ability to up-regulate the targeted death (ferroptosis) of DNA damaged stem cells in the gut, thereby reducing cancer risk. Our novel findings indicate that highly fermentable fiber, which generates butyrate (a microbial fermentation product) in the colon, has a protective effect when combined with long-chain n-3 polyunsaturated fatty acids (PUFA) found in fish oil. Specifically, n-3 PUFA and butyrate synergistically induce a novel p53-independent, GPX4-phospholipid oxidation-ferroptosis mediated pathway. These findings emphasize the need to examine both the fat and fiber composition of diets to promote the targeted deletion of cancer stem cells in the gut.
R. S. Chapkin, S. L. Navarro, M. A. J. Hullar, J. W. Lampe, Diet and gut microbes act coordinately to enhance programmed cell death and reduce colorectal cancer risk. Digestive Dis. Sci. 65, 840–851 (2020).
To Academic Professional Track Faculty