2013 Scientific Report

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VARI | 2013 Research Interests Renal cell carcinoma (RCC) is the most common type of cancer that arises within the adult kidney, and the tumors can be separated into categories based on the morphology of their cells. Clear cell RCC is the most common subtype, constituting 70–80% of renal tumors. Papillary RCC, which can be divided into type 1 and type 2, is the next most common subtype, representing 10–15%. Chromophobe RCC represents about 5% of renal tumors; other renal cell carcinomas are either unclassifiable by conventional means or represent rare subtypes. The latter include transitional cell carcinoma of the renal pelvis, renal medullary tumor, tubulocystic carcinoma, Xp11.2 translocation-associated tumor, collecting duct tumor, adult Wilms tumor, mixed epithelial and stromal tumor/cystic nephroma, and the usually benign renal oncocytoma and angiomyolipoma. Several decades of kidney cancer research indicate that the genetic mutations that accumulate within the tumor cells differ depending on the particular subtype. Overall, the laboratory is interested in identifying the genetic mutations present in renal cancer cells and in understanding how the different mutations transform normal cells into cancerous cells. We also want to understand the features associated with the most aggressive renal tumors. The analysis of papillary type 2 tumors (PRCC2) is one current focus. This is an aggressive subtype that has no effective treatment. Individuals who inherit a rare germline mutation in the fumarate hydratase gene (FH) are predisposed to develop this cancer. However, most PRCC2 tumors arise in the general population and do not contain that mutation. The genetic defects that lead to formation of sporadic PRCC2 tumors in the general population are not known. We have recently discovered that the transcription factors NRF1 and NRF2 (nuclear factor–erythroid-related factors 1 and 2) are activated in type 2 papillary RCC but not other subtypes of RCC. NRFs are key mediators of the adaptive detoxification response, and they regulate the many aspects of cellular detoxification and cell metabolism. NRF1 and NRF2 become activated as cells are exposed to electrophilic and reactive oxygen insults. NRFs then activate the transcription of a crucial set of enzymes that promotes cell survival by clearing toxic metabolites and xenobiotics. The FH mutations present in hereditary PRCC2 tumors result in high levels of intercellular fumarate. We have found that the NRF transcription factors become activated as fumarate, a reactive molecule, chemically modifies proteins at their exposed cysteine residues, a process termed succination (Figure 1). The modification of proteins by fumarate leads to NRF activation in these tumors. Sporadic PRCC2 tumors frequently lack FH mutations, so the mechanisms by which NRF is activated in these tumors is unclear. Both the mechanism by which NRF activation occurs in PRCC2 tumors and the functional connection between NRF activation and tumor cell survival are current focuses of the laboratory. We are also interested in the genetic mechanisms that give rise to the chromophobe subtype of renal tumors. Individuals who inherit a rare germline mutation in the folliculin gene (FLCN) are predisposed to chromophobe renal cancer. The mRNA profiles of tumors from such individuals gave clues that FLCN has a role in the energy sensing network, particularly in mitochondrial function. The connection between FLCN loss of function and tumor cell development is another focus. The tools that we use to study renal tumor development include a blend of computational modeling, molecular biology, and genetics. The genetic analysis of tumor cells typically includes the analysis of large amounts of DNA sequencing, mRNA expression profiling, and DNA copy number data. Therefore, we develop and apply new computational tools that can assist in extracting the significant biological information from these data sets, with a goal of understanding how cancer cells differ from normal cells at the molecular level. 23
Van Andel Research Institute | Scientific Report Figure 1 Figure 1: Mechanism of NRF2 activation in hereditary papillary renal cell carcinoma. NRF2 is a transcription factor that can migrate to the nucleus and activate the transcription of detoxification genes such as AKR1B10. Low levels of NRF2 are maintained by KEAP1 and CUL3. KEAP1 and CUL3 are required for NRF2 ubiquitination and degradation. This process is disrupted in cells with fumarate hydratase (FH) mutations. The normal biochemical activity of fumarate hydratase and succinate dehydrogenase are shown as part of the mitochondrial TCA cycle. In cells with FH mutation, excess fumarate is exported from the mitochondria and reacts with cysteine residues on KEAP1 (rounded rectangle). Modified KEAP1 is ubiquitinated and degraded. This prevents NRF2 from being degraded, and so nuclear levels of NRF2 increase. Recent Publications Farber, Leslie J., Kyle Furge, and Bin Tean Teh. 2012. Renal cell carcinoma deep sequencing: recent developments. Current Oncology Reports 14(3): 240–248. Klomp, Jeff A., and Kyle A. Furge. 2012. Genome-wide matching of genes to cellular roles using guilt-by-association models derived from single sample analysis. BMC Research Notes 5: 370. Ong, Choon Kiat, Chutima Subimerb, Chawalit Pairojkul, Sopit Wongkham, Ioana Cutcutache, Willie Yu, John R. McPherson, George E. Allen, Cedric Chuan Young Ng, Bernice Huimin Wong, et al. 2012. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nature Genetics 44(6): 690–693. Zhang, Yu-Wen, Ben Staal, Karl J. Dykema, Kyle A. Furge, and George F. Vande Woude. 2012. Cancer-type regulation of MIG-6 expression by inhibitors of methylation and histone deacetylation. PLoS One 7(6): e38955. 24
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