Descripción del proyecto
Mecanismo de carcinogénesis en la leiomiomatosis hereditaria y el carcinoma de células renales
Las mutaciones de las enzimas del ciclo del ácido tricarboxílico de las mitocondrias predisponen al cáncer, lo que apunta a la hipótesis de que el metabolismo desregulado puede generar carcinogénesis. Las mutaciones en la fumarato hidratasa (FH) provocan leiomiomatosis hereditaria y carcinoma de células renales (LHCCR), que se caracteriza por la acumulación de fumarato, tumores cutáneos y uterinos y cáncer de riñón. Sin embargo, se desconocen los mecanismos por los que se produce la pérdida de FH y la acumulación de fumarato. El proyecto ONCOFUM, financiado con fondos europeos, aspira a arrojar luz sobre los mecanismos que sustentan la carcinogénesis específica de tejidos en la LHCCR. Los investigadores crearán un modelo murino con FH desactivada en varios tejidos y dilucidarán la consiguiente reprogramación específica de los tejidos. También estudiarán, con modelos celulares, las consecuencias moleculares de la pérdida de FH y realizarán un análisis de tumores de LHCCR para descubrir herramientas de diagnóstico y pronóstico y nuevas dianas antineoplásicas.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
50937 Koeln
Alemania