Project description
Mechanism of tumourigenesis in hereditary leiomyomatosis and renal cell cancer
Mutations of tricarboxylic acid cycle enzymes in mitochondria predispose to cancer, pointing to the hypothesis that dysregulated metabolism could drive tumourigenesis. Mutations in fumarate hydratase (FH) cause hereditary leiomyomatosis and renal cell cancer (HLRCC) characterised by fumarate accumulation, tumours of the skin and uterus and renal cancer. However, the mechanisms by which FH loss and fumarate accumulation cause tumours are unclear. The EU-funded ONCOFUM project aims to shed light on the mechanisms that underpin tissue-specific tumourigenesis in HLRCC. Researchers will create a mouse model with FH inactivated in multiple tissues and elucidate the ensuing tissue-specific reprogramming. Using cellular models, they will investigate the molecular consequences of FH loss and perform analysis of HLRCC tumours to find diagnostic and prognostic tools and new anticancer targets.
Objective
Cancer cells undergo profound metabolic changes. However, little is known about whether and how metabolic changes drive cancer. The discovery that mutations of Tricarboxylic Acid (TCA) cycle enzymes in mitochondria predispose to cancer gives evidence that dysregulated metabolism could drive tumorigenesis. Amongst these, mutations in Fumarate Hydratase (FH) cause Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), characterised by tumours of the skin and uterus, and renal cancer. Patients inherit one mutated copy of FH and loss of the wild-type (wt) allele occurs in tumours. Fumarate accumulation is the defining biochemical feature of these tumours. However, the mechanisms by which FH loss and fumarate accumulation lead to these tumours is unclear.
In ONCOFUM, I want to elucidate the mechanisms that underpin tissue-specific tumorigenesis in HLRCC. I hypothesise that HLRCC occurs via a two-step process. Initially, loss of the wt allele in carriers of a FH mutation leads to FH deficiency. However, most of these cells die and only cells in tissues with the appropriate metabolic hardware survive. In the second step, FH loss in permissive tissues leads to phenotypic changes that lead to cancer. To assess this hypothesis, we will generate a mouse model where we inactivate FH in multiple tissues and elucidate the ensuing tissue-specific reprogramming. Then, using cellular models, we will investigate the molecular consequences of FH loss. In parallel, we will perform a comprehensive analysis of HLRCC tumours to find diagnostic and prognostic tools, and new anticancer targets, which will be validated in vitro and in vivo.
The experimental framework developed in ONCOFUM will give unparalleled molecular insights into how cancer develops in different tissues in response to loss of FH and will lead to new therapeutic strategies for HLRCC, and, more generally for the many other cancers to which metabolic reprogramming contributes.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
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(opens in new window) ERC-2018-COG
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50937 Koeln
Germany
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