The dysregulated metabolic traits of cancer are not confined to malignant cells; solid tumors systemically reprogram their metabolism to create a unique metabolic microenvironment to sustain tumorigenic properties. Alterations in extrinsic and intrinsic signals in tumors dictate how metabolic rewiring occurs. Rewired metabolism not only provides selective advantage to malignant cells in nutrient-stressed and hypoxic environments, but also facilitates invasion, metastasis, immune suppression, drug resistance, and tumor-promoting epigenetic modifications. However, recent studies have highlighted an inherent complexity of dissecting metabolic mechanisms driving tumorigenesis. One aspect of this complexity is due to the impact of metabolic alterations on epigenetic modifications and DNA damage repair. Metabolic pathways responsible for regulating methyl and acetyl levels create a reciprocal feedback loop between metabolism and genetic reprogramming in tumors. We will dissect here how tumors rewire to provide substrates for chromatin regulation. Further, we will investigate mitochondrial metabolism and its role as a signaling organelle in this project. We expect that our studies focused on the effect of ROS on DNA damage, and regulation of NAD metabolism for sirtuin-mediated DNA damage repair will unravel novel role of tumor microenvironment.
The other aspect of complexity in metabolic reprogramming is due to intratumoral heterogeneity. Reactive stroma are important players in the metabolic interactions within the tumor microenvironment (TME). Cancer cells reprogram stromal cells to help meet there high bioenergetic demands via secreted metabolites, exosomes, proteins and lipids. Rewired cancer metabolism can also create an immunosuppressive microenvironment that actively inhibits antitumor response of T-cells and natural killer cells. Therefore, we will investigate using metabolic flux how we can reverse tumor-supporting properties of reactive stroma for therapeutic benefits. The unique composition of the TME has also come under scientific scrutiny leading to the discovery of cancer cells utilizing exosomes, extracellular proteins and apoptotic bodies as fuel sources. We expect that novel aims on non-canonical nutrient sources will allow selective targeting of cancer cells. Thus, strategies targeting TME metabolism will have the potential to illicit and systemic anti-tumor response in contrast to cancer-specific targets of antineoplastic drugs.