Optical imaging platform to unravel metabolic reprogramming of cancer: a path for improved treatments (METABOLIGHT)
Project Summary: Cancer cells undergo metabolic reprogramming in order to meet elevated energy requirements to fuel proliferation, thus resulting in their differential utilization of many essential metabolites compared to normal cells. Recent advancements in the field of cancer metabolic reprogramming demonstrated significant increase in efficiency of standard cancer treatments when combined with cancer metabolic inhibitors. However, tumor metabolic reprogramming remains poorly understood for the majority of cancers. Moreover, many recent reports revealed evidence that the metabolism of cancer cells in vitro can differ significantly from that of in vivo because in vitro models lack complexity of the tumor microenvironment. However, the progress of studying tumor metabolism in vivo is significantly hampered by the lack of efficient tools that allow real-time noninvasive imaging and quantification of metabolite absorption in animal models of cancer which closely reflect human pathologies. Here, we propose to develop a novel imaging platform that has several important advantages over the existing methods, and allows noninvasive evaluation of the uptake of several essential metabolites using highly sensitive and quantifiable bioluminescent imaging. The method is independent of radioactive and/or short-lived isotopes, less costly, and allows longitudinal monitoring of metabolite absorption during disease progression (e.g., cancer development or clinical intervention such as chemotherapy). We are working to expand this technology to develop novel probes to study uptake of several amino acids, fatty acids, and nucleosides that all play central role in cancer metabolic reprogramming. We are performing thorough validation of this platform in cells, healthy transgenic mice and murine animal cancer models to assure that the reagents fulfill the requirements for physiological behavior, stability, safety, and robust signal generation both in vitro and in vivo. We will then apply this platform to investigate the nutrient utilization in hepatocellular- and intra- hepatic cholangiocarcinomas (HCC and ICC) with the goal of understanding metabolic vulnerabilities of this deadly disease. This may lead to the generation of novel, effective treatments based on already existing cancer metabolic inhibitors; therefore, this novel platform has high clinical applicability.
NR is a pyridine-containing nucleoside and a component of vitamin B3, commonly used as a supplement. NR is one of the most studied precursors for the restoration of cellular NAD+ that plays a central role in cellular energy metabolism. NR supplementation demonstrated significant clinical potential in many metabolic and age-related disorders and is currently investigated in 50+ clinical trials. Thus, understanding the underlying mechanism of NR uptake by different cells and tissues is very important. However, this process is greatly limited by the lack of noninvasive tools and no tools currently exist for studies of NR uptake in vivo, limiting its clinical translation. We successfully developed and validated a bioluminescent NR (abbreviated as BiNR) uptake probe that could be used for non-invasive longitudinal imaging of NR uptake both in vitro and in vivo. We also developed novel assay that allows the use of our platform in clinical samples such as T-cells. This development obviates the use of cells and tissues that express luciferase and significantly expands the use of the platform. Using our novel BiNR probe, we investigated the role of NR uptake in T cells and several cancers. Our results emphasize the important role of powerful nutraceuticals like NR in cancer metabolism and the necessity to personalize their use in certain patient populations such as TNBC patients.