2013 Scientific Report

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.
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