The frequently altered expression of metabolism genes in solid tumors such as clear cell renal cell cancer (ccRCC) has reinforced the importance of dysregulated metabolism in driving tumor expansion. Indeed, constitutive activation of the hypoxia inducible transcription factor (HIF) through mutations in the von Hippel Lindau (VHL) tumor suppressor gene or through exposure to hypoxia, results in enhanced glucose uptake, glycolytic flux, lactate secretion and suppression of mitochondrial activity. Conversely, reactive oxygen species produced by the mitochondria stimulate HIF-dependent transcription, creating an intricate signaling loop that balances mitochondrial oxygen consumption with the cellular response to hypoxia. In addition to stimulating glycolysis while suppressing OXPHOS, hypoxia has also been demonstrated to stimulate de novo lipogenesis through reductive glutamine metabolism, although it has not yet known how this reductive glutamine metabolism contributes to lipid accumulation in solid tumors and the clear cell phenotype in ccRCC. Importantly, HIF-dependent metabolic changes have been exploited therapeutically, indicating that a more comprehensive understanding of HIF regulated metabolism may yield novel anti-cancer therapies. Oxidative metabolism, which broadly encompasses carbohydrate oxidation, glutamine oxidation, and fatty acid -oxidation, is controlled by a number of nuclear and mitochondrial transcription factors that together promote the biogenesis and enzymatic function of mitochondria and is often found repressed in many tumors including ccRCC. First identified for their role in promoting adaptive thermogenesis, the peroxisome proliferator activated receptor gamma coactivators PGC-1? and PGC-1 promote mitochondrial biogenesis and OXPHOS activity in a wide range of tissues by stimulating the transcriptional activation potential of a number of nuclear transcription factors. PGC-1? and PGC-1 are encoded by discrete genetic loci and exhibit both distinct and redundant transcriptional targets. Indeed, PGC-1? -/- mice exhibit multi-tissue defects in oxidative metabolism, indicating unique functions for PGC-1? that cannot be compensated for by PGC-1. Furthermore, PGC-1? deficient mice accumulate significantly more body fat than wild type mice, and develop fasting induced hepatic steatosis, suggesting an important role for PGC-1? in the regulation of lipid metabolism. While the functions of the PGC family have been extensively studied in normal physiology, their function in the context of malignancy has not been rigorously investigated. Our recent studies indicate that PGC-1? is suppressed in ccRCC through a HIF-?/Dec1 transcriptional axis. The suppression of PGC-1? in VHL-wild type renal proximal tubule cells is associated with reduced mitochondrial activity and acquisition of the clear cell (lipid and glycogen accumulation) phenotype, a histological hallmark of ccRCC. These findings provide the first evidence linking the clear cell phenotype to multiple aspects of renal tumorigenesis and raise the potential for PGC-1? stimulation as a novel therapeutic modality in the treatment of renal cell carcinoma, and potentially other solid tumors. The goals of this grant are to explore the molecular mechanisms governing lipid homeostasis in cancer, characterize their contribution to tumorigenesis and identify ways that they can be therapeutically targeted in solid tumors and determine how to best exploit them therapeutically.
Though accumulation of intracellular lipids is found in ccRCC and other solid tumors, how this accumulation is advantageous to tumorigenesis remains unclear. The severe reduction in mitochondrial respiratory activity in ccRCC makes it is unlikely that lipid droplets are a significant source of ATP production within the cell, and hypoxia suppresses fatty acid -oxidation. The goals of this grant are explore the mechanisms of lipid accumulation in solid tumors and determine how to best exploit them therapeutically.
| Tandon, Neha; Thakkar, Kaushik N; LaGory, Edward L et al. (2018) Generation of Stable Expression Mammalian Cell Lines Using Lentivirus. Bio Protoc 8: |
| Olcina, Monica M; Kim, Ryan K; Melemenidis, Stavros et al. (2018) The tumour microenvironment links complement system dysregulation and hypoxic signalling?. Br J Radiol :20180069 |
| Aguilera, Todd A; Giaccia, Amato J (2017) Molecular Pathways: Oncologic Pathways and Their Role in T-cell Exclusion and Immune Evasion-A New Role for the AXL Receptor Tyrosine Kinase. Clin Cancer Res 23:2928-2933 |
| Johnson, Rachelle W; Sowder, Miranda E; Giaccia, Amato J (2017) Hypoxia and Bone Metastatic Disease. Curr Osteoporos Rep 15:231-238 |
| Castellini, Laura; Moon, Eui Jung; Razorenova, Olga V et al. (2017) KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. Nucleic Acids Res 45:3674-3692 |
| VandeKopple, Matthew J; Wu, Jinghai; Baer, Lisa A et al. (2017) Stress-responsive HILPDA is necessary for thermoregulation during fasting. J Endocrinol 235:27-38 |
| Rankin, Erinn B; Giaccia, Amato J (2016) Hypoxic control of metastasis. Science 352:175-80 |
| Rankin, Erinn B; Giaccia, Amato J (2016) The Receptor Tyrosine Kinase AXL in Cancer Progression. Cancers (Basel) 8: |
| Johnson, Rachelle W; Finger, Elizabeth C; Olcina, Monica M et al. (2016) Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol 18:1078-1089 |
| Rankin, Erinn B; Nam, Jin-Min; Giaccia, Amato J (2016) Hypoxia: Signaling the Metastatic Cascade. Trends Cancer 2:295-304 |
Showing the most recent 10 out of 14 publications
