Project Funding Details

Understanding the genetic mechanisms that guide the evolution from a normal to a cancer cell may enable strategies of tumor prevention. In the kidney, the most common tumor type, named clear cell renal cell carcinoma (ccRCC), is derived from a specific cell subset. Somatic mutations that confer malignancy traits are progressively accumulated, starting from the first decade of life. The most common cancer-driver event in sporadic ccRCC is the disruption of the tumor suppressor gene and regulator of the response to hypoxia Von Hippel Lindau (VHL). When VHL mutations are inherited, they cause a tumor-predisposition syndrome characterized by a 70% lifetime risk of ccRCC. Our preliminary data show that the precursors of ccRCC accumulate somatic mutations faster than other kidney cell types and this excess of mutations is likely due to a rewiring of cellular metabolism in conditions of hypoxia (either due to micro-ischemic episodes or pseudo-hypoxia consequent to VHL-loss). These metabolic changes are amenable to pharmacological regulation. Therefore, we hypothesize that targeting specific metabolic pathways (e.g. conversion of glutamine into glutamate, excessive pyrimidine biosynthesis, production of the oncometabolite 2HG) may slow down mutation accumulation and tumor evolution in the kidney. First, we plan to demonstrate the causal relationship between metabolic changes downstream hypoxia in pre-cancer kidney cells and somatic mutagenesis underlying ccRCC. Secondly, we aim to provide the proof of concept that pharmacological targeting of specific metabolic pathways can reduce somatic mutagenesis in pre-cancer cells and eventually reduce penetrance of ccRCC in predisposed kidneys. The landscape of somatic mutations in pre-cancer and cancer genomes from the kidney of VHL patients and controls will be analyzed by exploiting my published method for somatic mutation detection in single genomes (WP1). The molecular mechanism leading to the observed mutation pattern will be elucidated by analyzing primary kidney cells (obtained from the urine) exposed to putative genotoxic conditions, such as hypoxia and metabolic alterations (WP2). The genotoxic effect of selected metabolic changes will also be assessed in vivo, in mice treated with hypoxia or diets that alter glutamine metabolism (WP3). Finally, specific strategies to reduce the impact of hypoxia-mediated metabolic changes on somatic mutation accumulation will be tested in primary kidney cells from VHL patients (WP4). We expect to dissect the molecular mechanism connecting kidney hypoxia, metabolic changes and loss of genome integrity and validate metabolic targets able to reduce somatic mutation accumulation and prevent ccRCC development in the kidney. While pharmacological targeting of metabolism is not a suitable strategy for kidney tumor prevention in the general population, this approach can be adopted for those patients affected by genetic diseases that induce predisposition to renal cell carcinoma, such as VHL and other inherited syndromes. These patients develop numerous kidney tumors that constitute the leading cause of death. Despite early diagnosis of the inherited disease and multiple decades required for ccRCC to develop, patients have no therapeutic options to reduce or delay tumor evolution. If proved effective, the presented strategy for tumor prevention will revolutionize the clinical management of VHL and other genetic diseases.