Characterization of a Novel Critical Interplay Between VHL Inactivation and Iron Metabolism in Clear Cell Renal Cell Carcinoma Tumorigenesis
Abstract
Background: Kidney cancer is a significant health concern to U.S. Veterans, their families, and the general American public due to high rates of diagnosis and death in both men and women. Most kidney cancer diagnoses and deaths are due to clear cell (cc) renal cell carcinoma (RCC). A unique common feature of ccRCC is a mutated von Hippel Lindau (VHL) gene. Animal models that recreate the biology of human VHL-mutated ccRCC provide a key research tool to minimize and improve experimentation in humans but, unfortunately, remain scarce. This proposal exploits a novel mouse modeling strategy based on our recent findings that suggest renal cell iron accumulation and VHL mutation work together to promote ccRCC development. Iron has known ability to cause DNA mutations and cell growth, and our lab and others have shown that the kidney has the highest body levels of protein machinery that imports iron into cells, which may make the kidney prone to iron overload. Renal iron accumulation occurs independently of total body iron levels or iron ingestion, and conditions that trigger renal iron accumulation are intriguingly also major risk factors for RCC (hypertension, obesity, diabetes, chronic kidney disease, hypoxia/low oxygen). Thus, renal iron accumulation may be a common molecular "link" that underlies different causes of RCC. Consistent with this role, experimental induction of high iron levels in the kidney and other body organs of rodents leads to cancers in only the kidney. Iron-induced rodent kidney tumors mimic human ccRCC in many features such as its "clear cell" appearance but lack a VHL gene mutation. To complement these observations, our research team has discovered high iron levels in human ccRCC compared to normal kidney or even other common cancers (e.g., breast cancer, colon cancer, prostate cancer, etc.). We have also discovered that VHL-mutated ccRCC cells, but not normal kidney cells, depend on iron for survival and growth; and intriguingly, that the VHL mutation itself is responsible for introducing this new iron requirement to ccRCC cells. These novel findings show us that there is a cooperative interaction ("interplay") between VHL mutation and abnormal iron accumulation for ccRCC cell survival and growth. Study Design: The current proposal uses a novel mouse modeling strategy to further study the cooperative interplay between VHL mutation and iron accumulation in ccRCC. Although iron-induced mouse ccRCC tumors lack VHL mutation, it is technically feasible to introduce the VHL mutation into these tumors with genetic engineering approaches. Thus, instead of trying to create ccRCC tumors by introducing VHL mutation into mice (a strategy which by itself has failed), we will use a "reverse" modeling strategy that starts with mouse ccRCC tumors and introduces the VHL mutation to generate VHL-mutant ccRCC tumors. The current proposal will use this novel modeling strategy to answer several innovative and impactful questions: (1) How do VHL mutation and iron accumulation cooperate to enhance mouse ccRCC tumor development? (2) In what ways is the distinctive molecular and immunologic appearance of iron-induced ccRCC tumors influenced by VHL mutation? (3) In what ways (molecular and immunologic) are these mouse VHL-mutated iron-induced ccRCC tumors similar to human VHL-mutant ccRCC tumors? Specific tumor features that will be studied include the speed and frequency of tumor formation, the microscopic appearance of the tumors, the ability of the tumors to spread from the kidney, molecular and genetic tumor profiles, and types and amounts of immune cells in the tumors, the last of which will be invaluable to study immunotherapies in future. Finally, the proposal will elucidate the molecular mechanism by which VHL mutation introduces a heightened iron requirement to ccRCC cells, by testing if the dependency of VHL-mutant ccRCC on high HIF-2alpha protein also mediates its dependency on iron. Innovation an
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010721
Entities
People
- Eric Kauffman
Organizations
- United States Army