Cancer cannot be defined as a single disease, but rather a collection of diseases with distinct histopathological and genetic features. Nevertheless, all cancers share many common traits, among which dysregulated metabolism is a hallmark. It is now clear that several metabolic pathways converge to provide cancer cells with the nutrients required for unrestrained growth and proliferation, and to maintain redox homeostasis. Yet, the extent at which dysregulated metabolism contributes to the cancerous transformation is poorly understood.
Mutations in the Tricarboxylic acid (TCA) cycle enzymes Succinate Dehydrogenase (SDH), Fumarate Hydratase (FH), and Isocitrate Dehydrogenase (IDH) have been shown to cause hereditary and sporadic forms of cancer. These discoveries provide evidence of an unanticipated cancer-causing role of mutated metabolic enzymes.
Our laboratory seeks to understand the contribution of dysregulated metabolism to age-associated disorders, in particular focusing on cancer. A part of the lab is investigating how the loss of FH causes Hereditary Leiomyomatosys and Renal Cell Carcinoma (HLRCC). While rare, HLRCC provides a tractable paradigm where it is clear that a metabolic event initiates cancer. Furthermore, HLRCC individuals represent an unmet need in terms of cancer prevention and management. Another part of the lab is working on the metabolic determinants of cancer initiation and progression. These findings and approaches can extend to other models of ageing and age-related diseases, to identify metabolic markers of disease and to establish novel therapeutic strategies and diagnostic tools.
Our work has multiple implications:
(1) it will provide a mechanistic understanding of the role of metabolism and small molecule metabolites in human diseases;
(2) it will generate experimental and computational tools to identify metabolic vulnerabilities that we can use as pharmacological targets for cancer therapy;
(3) it will apply metabolomics and multi-omics analyses, to mouse and human models to identify metabolic markers of disease initiation for clinical application in early detection and for patient stratification.