Contributors: Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille); Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret Lille (UNICANCER/Lille); Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); Laboratoire de Physiologie Cellulaire - U 1003 (PHYCELL); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille; Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA); Centre National de la Recherche Scientifique (CNRS); Institut Pasteur Paris (IP); Lithuanian University of health Sciences (LSMU); Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB; Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); Pathogénie microbienne moléculaire; Institut Pasteur Paris (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM); Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host; Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047); Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS); Toxines bactériennes - Bacterial Toxins; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047); Pôle Biomics (C2RT); Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT); Institut Pasteur Paris (IP)-Institut Pasteur Paris (IP); Indian Institute of Technology Jodhpur (IIT Jodhpur); Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12); CHU Henri Mondor Créteil; Funding support for this research was provided by the follow-ing grants: BpiFrance (grant number R21014EE / RVF21001EEA), Fondation i-SITE (grant number R20086EE / RAK20024EEA), Fondation pour la Recherche Médicale (grant number EQU202103012718), Inserm - Grand Programme Transversal Microbiote (grant number R17075EK/RSE17075EKA and R21091EK/RSE21091EKA), ITMO Cancer AVIESANPlan Cancer (grant number HTE201601,C16067ES/ASC16067ESA) and Région Hauts-de -France START-AIRR program (grant number Start’AIRR- 20-003). We thank the ONCOLille Institute. This work is supported by a grant from Contrat de Plan Etat-Région CPER Cancer 2015-2020.
Abstract: International audience ; Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land’s cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.
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