ONCOFUM
Financiado
Integrating the tissue specificity and chronology of hereditary renal cancer pre...
Integrating the tissue specificity and chronology of hereditary renal cancer predisposition
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 c...
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.
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Duración del proyecto: 72 meses
Fecha Inicio: 2019-02-20
Fecha Fin: 2025-02-28
Fecha Fin: 2025-02-28
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2019-02-20
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2018-COG:
ERC Consolidator Grant
Cerrada
hace 6 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
KLINIKUM DER UNIVERSITAET ZU KOELN
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
356.43K€ |
Participante
658.88K€ |
Participante