Colorectal cancer (CRC); Flux analysis; Fusobacterium nucleatum; Genome-scale metabolic model (GEM) reconstruction; Metabolic modeling and data integration; Systems Biology; Microbiology; Immunology and Microbiology (miscellaneous); Microbiology (medical); Infectious Diseases
Abstract :
[en] Bacteria living inside the tumoral micro-environment play a crucial role in the development of cancer and its progression. Enrichment of Fusobacterium nucleatum in colorectal cancer (CRC) tissue has been acknowledged as a major driver of its proliferation and mortality. Representatives of the F. nucleatum species exhibit a remarkable variability, being linked to a growing list of diseases. In this process, cellular metabolism plays a key role, allowing bacterial cells to efficiently cope with an ever-changing environment. To date, however, a mechanistic understanding of its relationship(s) with virulence and/or cancer-associated phenotypes is missing. In this work we characterize the basal physiology of this bacterium by reconstructing an experimentally validated genome-scale metabolic model (GEM) to simulate the major phenotypical features of F. nucleatum in different nutritional conditions. Further, we used gene expression data obtained from in vitro models to contextualize this metabolic reconstruction and simulate relevant phenotypes such as its interaction with human cells. Our analyses revealed that adhesion triggers a metabolic rewiring, with suppression of branched-chain amino acid catabolism and increased uptake of specific nutrients (e.g., methionine and serine), while invasion leads to a partial reactivation of central carbon and nitrogen pathways. Moreover, we identified shifts in short-chain fatty acid production and redox balance that may contribute to bacterial persistence and modulation of the tumor microenvironment.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Giovannini, Michele ; Department of Biology, University of Florence, Florence, Italy
Bosi, Emanuele; Department of Earth, Environmental and Life Sciences, University of Genoa, Genoa, Italy
Vieri, Walter; Department of Agricultural Food Environment and Forestry Sciences and Technologies, University of Florence, Florence, Italy
PRESTA, Luana ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Health, Medicine and Life Sciences > Team Thomas SAUTER ; iMEAN, Toulouse, France
Viciani, Elisa; Wellmicro Srl, Bologna, Italy
Bernabei, Ilaria; Department of Biology, University of Florence, Florence, Italy
Nannini, Giulia; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Stares, Mark D; Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, United Kingdom
Browne, Hilary; School of Microbiology, University College Cork, Ireland ; APC Microbiome Ireland, University College Cork Ireland
Lawley, Trevor D; Host-Microbiota Interactions Laboratory, Wellcome Sanger Institute, Hinxton, United Kingdom
SAUTER, Thomas ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Health, Medicine and Life Sciences (DHML)
LETELLIER, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Health, Medicine and Life Sciences (DHML)
KARTA, Jessica ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Health, Medicine and Life Sciences > Team Elisabeth LETELLIER
Amedei, Amedeo; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Fani, Renato; Department of Biology, University of Florence, Florence, Italy
Fondi, Marco; Department of Biology, University of Florence, Florence, Italy
Forskningsrådet för Arbetsliv och Socialvetenskap Fund for Southern Communities
Funding text :
The research was founded with a grant from the regional contribution of 201CThe Programma Attuativo Regionale (Toscana), funded by FAS (now FSC), grant MICpROBIMM. Funding was awarded by R. Fani and A. Amedei.
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