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Integrating the tissue-specificity and chronology of hereditary renal cancer predisposition

Descrizione del progetto

Meccanismo di tumorigenesi nella leiomiomatosi ereditaria e nel carcinoma a cellule renali

Le mutazioni degli enzimi del ciclo degli acidi tricarbossilici nei mitocondri predispongono al cancro, indicando l’ipotesi che un metabolismo disregolato potrebbe guidare la tumorigenesi. Le mutazioni nella fumarato idratasi (FH, Fumarate Hydratase) provocano leiomiomatosi ereditaria e carcinoma a cellule renali (HLRCC) caratterizzati da accumulo di fumarato, tumori della pelle e dell’utero, nonché carcinoma renale. Tuttavia, i meccanismi con cui la perdita di FH e l’accumulo di fumarato provocano tumori non sono chiari. Il progetto ONCOFUM, finanziato dall’UE, si propone di chiarire i meccanismi che sono alla base della tumorigenesi tessuto-specifica nell’HLRCC. I ricercatori creeranno un modello murino con FH inattivato in più tessuti e chiariranno la conseguente riprogrammazione tessuto-specifica. Utilizzando modelli cellulari, studieranno le conseguenze molecolari della perdita di FH ed eseguiranno analisi dei tumori HLRCC per trovare strumenti diagnostici e prognostici e nuovi bersagli antitumorali.

Obiettivo

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.

Meccanismo di finanziamento

ERC-COG - Consolidator Grant

Istituzione ospitante

KLINIKUM DER UNIVERSITAET ZU KOELN
Contribution nette de l'UE
€ 1 339 814,62
Indirizzo
Kerpener Strasse 62
50937 Koeln
Germania

Mostra sulla mappa

Regione
Nordrhein-Westfalen Köln Köln, Kreisfreie Stadt
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 1 339 814,62

Beneficiari (2)