Metabolic reprogramming of the tumor microenvironment and therapy resistance

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PROJECT SUMMARY/ABSTRACT Metastatic ovarian cancer (OvCa) is the leading cause of death from gynecologic cancer. Despite aggressive chemotherapy and surgery, most patients (80%) experience intraabdominal progression or recurrence to visceral adipose tissue in the abdominal cavity. For more than 15 years, my laboratory has concentrated on elucidating the biology of OvCa metastasis, focusing on understanding how deregulation of the tumor microenvironment (TME) promotes OvCa metastasis and chemotherapy resistance. We defined the contribution of multiple stromal cell types to metastasis, revealing a critical role for a methyltransferase (NNMT) in the reprogramming of normal fibroblasts into cancer-associated fibroblasts through metabolic remodeling. Additionally, we answered the decades-old question of why abdominally metastasizing tumors have a propensity to metastasize to the omentum, finding that adipokines attract cancer cells to adipose tissue, and that adipocytes provide long-chain fatty acids to cancer cells for energy production through β-oxidation. However, fundamental questions remain about metabolic processes in OvCa progression. How are OvCa metastases metabolically different from primary tumors? Which fuels/metabolites are altered after chemotherapy, and how do they contribute to chemotherapy resistance? Given that immunotherapies are effective in several epithelial tumors, one of the more puzzling and timely questions is why checkpoint inhibitors are ineffective in OvCa. My hypothesis is that cancer associated adipocytes contribute to therapy resistance and immune effector cell exhaustion through the lipid-driven metabolic reprogramming of the TME. We have adapted methods to perform in vivo metabolic flux analysis in OvCa patients, by infusing labeled metabolites (non-radioactive 13C-glucose, acetate) and are working on methods to optimize compartment resolved metabolomics on tumor tissue using imaging mass spectrometry. These data will allow us to define metabolic changes in cancer, immune, and stromal cells before and after neoadjuvant chemotherapy. The hypotheses generated by these studies will be tested with wide-ranging experimental approaches using primary organotypic 3D cultures and mouse models. Our experimental approach will span functional cellular assays (to study adhesion, migration, and invasion), confocal imaging, biochemical activity assays, and newly devised methods to test the functionality of natural killer cells, T-cells, and macrophages in vitro and in vivo. Compartment-specific insights into metabolic changes in the tumor organ will be employed to develop high-throughout screening campaigns. These should discover small molecule inhibitors that can be optimized through an established and structured process towards clinical testing. We believe that, by targeting metabolic processes identified in the tumor organ, we can greatly enhance anti-tumor therapy response in OvCa, potentially halting the inexorable progression characteristic of this deadly disease.