skip to content

Specific Programmes



1. Identification of novel mechanisms of tumorigenesis in FH-deficient renal cancer.

FH mutations cause Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), a cancer predisposition syndrome characterised by benign tumours of smooth muscle in the skin and uterus, plus an aggressive and highly metastatic form of renal cancer. HLRCC patients inherit a mutant copy of FH and cancer formation is caused by the loss of the wild type allele (loss of heterozygosity, LOH). Our laboratory aims to address why the loss of the FH predisposes to cancer in specific tissues, with distinct severity and progression.

By capitalising on novel cellular and murine models that we generated, we characterised the metabolic changes caused by FH loss on central carbon metabolism (Gonçalves et al., Metabolic Engineering, 2018) and on mitochondrial function (Tyrakis et al., Cell Reports, 2017). We have also investigated the consequences of accumulation of fumarate, which we had previously demonstrated to be a unique biochemical feature of these tumours (Frezza et al., Nature, 2011; Zheng et al., Cancer & Metabolism, 2013), on cell behaviour. We found that fumarate drives an epithelial-to-mesenchymal transition (EMT) via the epigenetic suppression of a family of antimetastatic miRNA (Sciacovelli et al., Nature, 2016). We were also able to show that fumarate affects the response of cells to DNA damaging agents, indicating that when accumulated, fumarate can disrupt DNA repair (Johnson et al., Cell Death & Disease, 2018). These works laid the foundation for a new branch of research in our lab dedicated to the investigation of the mechanisms underpinning tissue-specific carcinogenesis upon FH loss and to uncovering the role of fumarate as a bona fide oncometabolite.


Oncogenic signalling in FH-deficient cells.

Upon FH loss, fumarate accumulation inhibits the activity of aKGDDs. For instance, fumarate inhibits prolyl hydroxylases (PHDs), causing the stabilisation of the alpha subunit of a family of hypoxia inducible factors (HIFs) even in the presence of normal oxygen levels. In the nucleus, fumarate accumulation induces a profound epigenetic reprogramming due to the inhibition of both DNA and histone demethylases (TETs and KDMs respectively). In particular, the inhibition of the demethylation of miR200 was shown to trigger an epithelial-to-mesenchymal transition (EMT) in FH-deficient cells. Fumarate can also activate the transcription factor NRF2 by covalently binding to its negative regulator Keap1 through a modification called succination.



2. Metabolic reprogramming of cancer


2.1. Mitochondrial dysfunction in cancer

The observation that cancer cells rewire their metabolism has now been corroborated by several lines of evidence (Pavlova & Thompson, Cell metabolism, 2016). Yet, whether cancers share common metabolic features, and the extent to which these features contribute to carcinogenesis is still unclear. To address these questions, we started a comprehensive analysis of the metabolic landscape of cancer to distil metabolic signatures shared by different cancer types. We found that the suppression of oxidative phosphorylation (OXPHOS), a core mitochondrial pathway, is common in solid cancers characterised by poor clinical outcome. Importantly, we identified a negative correlation between the expression of OXPHOS and of genes belonging to the epithelial-to-mesenchymal (EMT) transcriptional signature (Gaude & Frezza, Nature Communications, 2016). Given the established role of EMT in cancer metastasis and as a marker of poor prognosis, our results could explain why tumours with low OXPHOS have a poor clinical outcome.

In order to investigate this connection between mitochondrial dysfunction and malignant features, we capitalised on a model of mitochondrial dysfunction caused by a mitochondrial DNA (mtDNA) mutation in the gene coding for ATP6. We engineered these cells to control the level of heteroplasmy of mtDNA, to obtain syngeneic cells with a varying degree of mitochondrial dysfunction. We observed an increase in migration properties proportional to the degree of mitochondrial dysfunction (Gaude et al., Molecular Cell, 2018), in agreement with the predictions of our computational study (Gaude & Frezza, Nature Communications, 2016). This work paved the way for a renewed connection between mitochondrial dysfunction and EMT, with direct implications for cancer biology, which we are currently exploring.

2.2 The metaboic reprogramming of renal cancer.

Our work has shown how understanding the metabolic features of HLRCC, a rare type of renal cancer, can elucidate mechanisms of disease. Part of the lab is applying this knowledge to investigate the role of dysregulated metabolism in clear cell renal cancer (ccRCC), which is a much more common type of renal cancer characterized by major changes to metabolism (Fig. 3 and Yang et al, Nature Reviews Nephrology 2020). In this part of the programme we will expand our experimental approaches to this type of renal cancer, capitalising on the collaboration with clinical academics, focusing on the identification of metabolic features of the disease that we can use as markers for patient stratification and as targets for anticancer therapy.


The metabolic reprogramming in renal cancer.

Schematics of the major metabolic alterations in ccRCC. Glycolysis catabolises glucose to form pyruvate and yields intermediates for entry into the pentose phosphate pathway, the tricarboxylic acid (TCA) cycle and lipid synthesis. The pentose phosphate pathway provides reducing equivalents (NADPH) and precursors for nucleotide synthesis. Upregulation of this pathway is associated with aggressive ccRCC and poor patient outcomes. The TCA cycle is a series of reactions that fully oxidize carbohydrates, lipids and proteins and generate reducing equivalents (NADH) for the electron transport chain to generate ATP. The TCA cycle intermediates are also a source of precursors for lipid and amino acid biosynthesis. Downregulation of TCA cycle genes correlates with aggressive ccRCC and poor patient outcomes. Lipid synthesis is required for energy stores and synthesis of cell membrane components, whereas lipid degradation via the β-oxidation pathway is required for release of energy stores and to generate acetyl-CoA, which then feeds the TCA cycle. In RCC, downregulation of β-oxidation is associated with poor patient outcomes. Upregulation of fatty acid synthesis also correlates with aggressive disease and poor outcomes in RCC. Reversed flow of the canonical TCA cycle (known as reductive carboxylation, purple arrows) enables glutamine-derived α-ketoglutarate to be metabolized to form citrate, which can generate lipogenic acetyl-CoA once exported into the cytosol. Cancer cells with mitochondrial defects, such as fumarate hydratase (FH)-deficient and succinate dehydrogenase (SDH)-deficient RCC, predominantly utilize this pathway to support cell growth. αKGDH, α-ketoglutarate dehydrogenase; ACO2, aconitase; CoA, coenzyme A; FBP1, fructose-1,6-bisphosphatase 1; GDH, glutamate dehydrogenase; GLS, glutaminase.  This figure is adapted from Yang et al, Nature Reviews Nephrology 2020.