The role of mitochondrial dysfunction in cancer has been debated for over a century. The discovery that mutations of core metabolic enzymes in the mitochondria, such as Fumarate Hydratase (FH), cause renal cancer strongly indicates that mitochondrial dysfunction can drive cancer. Today, I will provide an overview of our recent findings about the molecular mechanisms through which mitochondrial dysfunction can drive transformation. In particular, using a novel genetically modified mouse model, I will show that FH loss has different outcomes in different tissues, and whilst the kidneys are very robust to FH loss, other tissues don’t tolerate FH loss and here, FH-deficient cells are negatively selected. Our work provides some insights into potential mechanisms of tissue-specific tumorigenesis.
Dr. Christian Frezza is the Alexander von Humboldt Professor of Metabolomics in Ageing, at CECAD, at the University of Cologne. He studied Medicinal Chemistry at the University of Padova, Italy, and gained his MSc in 2002, after a period of research on mitochondrial toxicity induced by photoactivable anticancer drugs. Christian then joined the laboratory of Luca Scorrano in Padova to start a PhD on mitochondrial dynamics and apoptosis. In 2008, he moved to the Beatson Institute of Cancer Research in Glasgow as the recipient of an EMBO Long-Term Fellowship, where he investigated the role of mitochondrial defects in tumorigenesis. He moved to the MRC Cancer Unit in 2012 as a tenure track Group Leader and became a Programme Leader in 2017. In 2021, as the recipient of the Alexander Von Humboldt professorship, he moved his laboratory to CECAD at the University of Cologne.
By using a combination of biochemistry, metabolomics, and systems biology, he investigates the role of altered metabolism in cancer initiation and progression. His aim is to exploit these findings to establish novel therapeutic strategies and diagnostic tools for cancer.
X handle: @Frezzalab
Brief summary of the lines of research
Since starting my independent research group in 2012, I have pursued the emerging paradigm that dysregulated cellular metabolism can contribute to, and in some cases, promote carcinogenesis. Our work focuses on the dysregulation of mitochondrial metabolism, a key feature of tumorigenesis with yet unclear molecular underpinnings. This work is the result of a natural progression of my longstanding interest in mitochondria, which started during my PhD with Luca Scorrano, where I contributed to a new understanding of the link between mitochondrial dynamics and apoptosis (Frezza et al Cell 2006), and later during my post-docs with Eyal Gottlieb, where I laid the foundation of my current work on Fumarate Hydratase (Frezza et al Nature 2011). Our work has begun to contribute to a new understanding of mechanisms of tumour initiation and progression, which are invariably characterised by profound metabolic changes (Gaude et al, Nat Comms 2016), but whose role is only partially understood. Our work provided evidence that fumarate, a metabolite that accumulates in fumarate hydratase-deficient cancer cells, triggers the epithelial-to-mesenchymal transition (Sciacovelli et al, Nature 2016), and inflammation (Zecchini et al, Nature 2023), events critical for tumorigenesis. These findings demonstrate that metabolic reprogramming of cancer is not merely an epiphenomenon of cell transformation but, rather, that it can actively contribute to the activation of oncogenic signalling cascades. Additional work(Gaude et al, Mol Cell 2018, Ryan et al, eLife 2021, Sciacovelli et al Nat Comms 2022) corroborated the relevance of dysregulated mitochondrial metabolism in driving oncogenic processes. A key feature of our work is the combination of multidisciplinary approaches, from hard-core mitochondrial biochemistry to systems biology, and metabolomics. We also strive to apply our results to clinically relevant contexts.