Title: The role of Fumarate Hydratase loss and fumarate accumulation in the predisposition to renal cancer
Funder: Cancer Research UK

Abstract: Background During tumorigenesis cancer cells undergo profound metabolic changes. However, little is known about whether and how these metabolic changes contribute to transformation. The discovery that mutations of Tricarboxylic Acid (TCA) cycle enzymes in mitochondria predispose to cancer provides compelling evidence that in some circumstances dysregulated metabolism could drive tumorigenesis. Amongst these, mutations in the enzyme Fumarate Hydratase (FH) cause Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a cancer predisposition syndrome characterised by tumours of the skin and uterus, and an aggressive and metastatic form of renal cancer. Understanding how FH loss predisposes to cancer is key to understand the link between dysregulated metabolism and cancer. We recently investigated the consequences of FH loss in mouse and human cancer cell lines. We have shown that upon FH loss cells undergo profound metabolic changes that are required to overcome the defects caused by the truncation of the TCA cycle. In parallel, these changes allow the aberrant accumulation of fumarate, the substrate of FH, which can activate a series of oncogenic signalling cascades, acting as an oncometabolite. However, the mechanisms by which FH loss and fumarate accumulation lead to transformation are still unclear. Aims In this research programme I want to elucidate the mechanisms that underpin tumorigenesis in HLRCC. I hypothesise that HLRCC develops in a two-step process. First, upon FH loss only cells with the appropriate metabolic hardware survive. In the second step, FH loss and the subsequent fumarate accumulation lead to a cascade of events, propagated in a hierarchical fashion, that lead to cancer. Methods To assess this hypothesis, we will generate a mouse model and human cell lines where FH can be inactivated in an inducible manner, and elucidate the ensuing cellular reprogramming in a time-resolved fashion, using a combination of metabolomics, transcriptomics, and epigenetic analyses. In parallel, we will perform a comprehensive analysis of HLRCC tumours to identify diagnostic and prognostic tools that will be cross-validated in vitro and in vivo models that we will generate. How the results of this research will be used The experimental framework developed in this proposal will give unparalleled molecular insights into how cancer develops in response to loss of FH and may lead to new therapeutic strategies for HLRCC, and, more generally for the many other cancers to which metabolic reprogramming contributes.

Lay abstract: Background During tumorigenesis cancer cells undergo profound metabolic changes. However, little is known about whether and how these metabolic changes contribute to transformation. The discovery that mutations of Tricarboxylic Acid (TCA) cycle enzymes in mitochondria predispose to cancer provides compelling evidence that in some circumstances dysregulated metabolism could drive tumorigenesis. Amongst these, mutations in the enzyme Fumarate Hydratase (FH) cause Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a cancer predisposition syndrome characterised by tumours of the skin and uterus, and an aggressive and metastatic form of renal cancer. Understanding how FH loss predisposes to cancer is key to understand the link between dysregulated metabolism and cancer. We recently investigated the consequences of FH loss in mouse and human cancer cell lines. We have shown that upon FH loss cells undergo profound metabolic changes that are required to overcome the defects caused by the truncation of the TCA cycle. In parallel, these changes allow the aberrant accumulation of fumarate, the substrate of FH, which can activate a series of oncogenic signalling cascades, acting as an oncometabolite. However, the mechanisms by which FH loss and fumarate accumulation lead to transformation are still unclear. Aims In this research programme I want to elucidate the mechanisms that underpin tumorigenesis in HLRCC. I hypothesise that HLRCC develops in a two-step process. First, upon FH loss only cells with the appropriate metabolic hardware survive. In the second step, FH loss and the subsequent fumarate accumulation lead to a cascade of events, propagated in a hierarchical fashion, that lead to cancer. Methods To assess this hypothesis, we will generate a mouse model and human cell lines where FH can be inactivated in an inducible manner, and elucidate the ensuing cellular reprogramming in a time-resolved fashion, using a combination of metabolomics, transcriptomics, and epigenetic analyses. In parallel, we will perform a comprehensive analysis of HLRCC tumours to identify diagnostic and prognostic tools that will be cross-validated in vitro and in vivo models that we will generate. How the results of this research will be used The experimental framework developed in this proposal will give unparalleled molecular insights into how cancer develops in response to loss of FH and may lead to new therapeutic strategies for HLRCC, and, more generally for the many other cancers to which metabolic reprogramming contributes.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS