Due to vascular insufficiency, solid tumors frequently harbor domains where cells have limited access to oxygen and blood-borne nutrients. Molecular oxygen (O2) is an essential nutrient serving as a key substrate for mitochondrial ATP production and numerous intracellular biochemical reactions. O2 deprivation (hypoxia) triggers complex adaptive responses at the cellular, tissue, and organismal levels to match O2 supply with metabolic and bioenergetic demands. In the face of hypoxic stress, mammalian cells temporarily arrest cell cycle progression, reduce energy consumption, and secrete survival and pro-angiogenic factors. These events are coordinated by engaging multiple, evolutionarily conserved molecular adaptations mediated by metabolic transitions, the hypoxia-inducible factor (HIF) transcriptional regulators, mTOR signaling, autophagy, and endoplasmic reticulum (ER) stress responses. The overall goal of our research is to elucidate molecular mechanisms by which changes in O2 and nutrient availability modulate normal tissue homeostasis and mammalian pathology, with a particular focus on cancer cell metabolic reprogramming, metastasis, and interactions between malignant and infiltrating immune cells.
Sites of inflammation frequently become hypoxic due to vascular damage, edema, and heightened metabolic activity of bacteria and infiltrating immune cells. We have previously shown that low O2 levels render pancreatic and liver tissue more “permissive” for neoplastic initiation and progression, and now study how oxygen availability influences the recruitment of immune cells, such as B cells, T cells, macrophages and NK cells to tumors of the pancreas, liver, kidney and connective tissues that generate sarcomas. Of note, we recently determined that B cells play a more essential role in pancreatic cancer progression than previously appreciated, and influence cytotoxic T cell activity. This observation has launched multi-center clinical trials using B cell inhibitors in conjunction with standard of care, such as gemcitabine and abraxane. Finally, “metabolic symbioses” between tumor and other cells within the microenvironment (immune cells, endothelial cells, fibroblasts) need to be further characterized to enhance the efficacy of targeted and immuno-therapies, to expand the number of patients deriving benefit from these approaches.
Because a solid tumor cannot grow unless it acquires new blood vessels from surrounding host tissues, the HIFs are necessary for tumor progression, given that they regulate blood vessel formation. We have recently shown that HIFs (and metabolic changes they coordinate) are also clearly important for tumor metastasis. In addition to studying HIFs and metabolism in genetically engineered mouse models, we are also evaluating metabolomics in human patient samples, focusing on specimens acquired from individuals with renal clear cell carcinoma, sarcoma, pancreatic ductal adenocarcinoma, and liver cancer. The goal is to integrate our understanding of metabolic adaptations with documented changes in intracellular signaling, organelle function, and genome-wide mutations. Cancer cell metabolic reprogramming is directly impacted by variable O2 and nutrient levels in solid tumors, and must be integrated with other processes, such as changes in the epigenome. Our ongoing studies will delineate each of these pathways, hoping to further exploit them for therapeutic benefit.