Genetics and cell biology
This Unit aims at understanding the metabolic reprogramming of cancer, identifying metabolic vulnerabilities in malignancies and determining how the metabolic landscape of the tumour microenvironment affects anti-tumour immune responses.
Cancer figures among the leading cause of morbidity and mortality in the world. Alterations in the acquisition and metabolism of nutrients are recognized as hallmarks of cancer development and progression. Many, if not all, oncogenes and tumour suppressor genes orchestrate a complex metabolic reprogramming in cancer cells, through changes in the regulation of expression and activity of enzymes and small-molecule transporters. These adaptive changes sustain increased acquisition and synthesis of cellular building blocks (e.g. sugars, fats, amino acids, etc) and are necessary for cancer cells to meet both biomass and energy demands imposed by uncontrolled cell growth as well as conditions of nutrient stress. Furthermore, metabolic alterations accompanying malignant transformation are instrumental to change the composition and function of the tumour microenvironment, such as tumour-infiltrating immune cells, which play a critical role in cancer development, progression, and control.
We aim at generating functional and mechanistic understanding of metabolic changes occurring in cancer and its microenvironment by using analytical chemistry, cell biology and computational modelling-integrated approaches. Identifying metabolic reprogramming essential for sustaining proliferative capacity of malignant cells and corrupting anti-tumour immune responses, our research will reveal novel and effective therapeutic targets and strategies for the improved treatment of cancer patients.
Torretta S, Scagliola A, Ricci L, Mainini F, Di Marco S, Cuccovillo I, Kajaste-Rudnitski A, Sumpton D, Ryan KM, Cardaci S. D-mannose suppresses macrophage IL-1β production. Nat Commun. 2020; 11(1):6343.
Scagliola A, Mainini F, Cardaci S. The Tricarboxylic Acid Cycle at the Crossroad Between Cancer and Immunity. Antioxid Redox Signal. 2020; 32(12):834-852.
Rizza S*, Cardaci S*, Montagna C, Di Giacomo G, De Zio D, Bordi M, Maiani E, Campello S, Borreca A, AA Puca, Stamler JS, Cecconi F and Filomeni G. S-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy. Proceedings of the National Academy of Sciences of the United States of America. 2018; 1091-6490 (* Co-First Authors)
Pablo Sierra Gonzalez, James O'Prey , Simone Cardaci, Valentin J A Barthet, Jun-Ichi Sakamaki, Florian Beaumatin, Antonia Roseweir, David M Gay, Gillian Mackay, Gaurav Malviya, Elżbieta Kania, Shona Ritchie, Alice D Baudot, Barbara Zunino, Agata Mrowinska, Colin Nixon, Darren Ennis, Aoisha Hoyle, David Millan, Iain A McNeish, Owen J Sansom, Joanne Edwards, Kevin M Ryan. Mannose impairs tumour growth and enhances chemotherapy. Nature. 2018, 563(7733):719-723.
Rizza S, Montagna C, Cardaci S, Maiani E, Di Giacomo G, Sanchez-Quiles V, Blagoev B, Rasola A, De Zio D, Stamler JS, Cecconi F, & Filomeni G. S- nitrosylation of the Mitochondrial Chaperone TRAP1 Sensitizes Hepatocellular Carcinoma Cells to Inhibitors of Succinate Dehydrogenase. Cancer Research. 2016;1538-7445
Sciacovelli M, Gonçalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, Drubbel AV, Theobald SJ, Abbo SR, Tran MG, Rajeeve V, Cardaci S, Foster S, Yun H, Cutillas P, Warren A, Gnanapragasam V, Gottlieb E, Franze K, Huntly B, Maher ER, Maxwell PH, Saez-Rodriguez J, & Frezza C. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature, 2016; ISSN: 0028-0836
Cardaci S, Zheng L, MacKay G, van den Broek NJF, MacKenzie ED, Nixon C, Stevenson D, Tumanov S, Bulusu V, Kamphorst JJ, Vazquez, A, Fleming, S, Schiavi, F, Kalna G, Blyth K, Strathdee D, & Gottlieb E. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nature Cell Biology, 2015;1476-4679
Zheng L, Cardaci S, Jerby L, MacKenzie ED, Sciacovelli M, Johnson TI, Gaude E, King A, Leach JD, Edrada-Ebel R, Hedley A, Morrice NA, Kalna G, Blyth K, Ruppin E, Frezza C, & Gottlieb E. Fumarate induces redox- dependent senescence by modifying glutathione metabolism. Nature Communications, 2015; 2041-1723
Cardaci S, Filomeni G, & Ciriolo MR. Redox implications of AMPK- mediated signal transduction beyond energetic clues. Journal of Cell Science. 2012;1477-9137
Cardaci S, Rizza S, Filomeni G, Bernardini R, Bertocchi F, Mattei M, Paci M, Rotilio G, & Ciriolo MR. Glutamine deprivation enhances antitumour activity of 3-bromopyruvate through the stabilization of monocarboxylate transporter-1. Cancer Research. 2012; 1538-7445