https://orcid.org/0000-0003-0400-882X
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ABSTRACT
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.
Acknowledgments
We would like to thank the BioImaging Center Lille platform for assistance with image acquisition. We thank monitoring platform studies of URC St Antoine (Pr T Simon for Vatnimad PHRC study), URC Henri Mondor (Pr F Canoui-Poitrine; for Valihybritest ANR study), Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09), Institut pour le Recherche sur le Cancer de Lille (IRCL), I-Site ULNE, INSERM (Messidore) and IBISA. This work benefited from equipment and services from the iGenSeq core facility (Genotyping and sequencing), at ICM.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Contributors
NOA and MC performed study design, acquisition of data, interpretation of data and statistical analysis. OB, SA, LA and NOA performed bacterial cultivation, cell culture, qRT-PCR analysis and in vivo tests. AV, IN, CM, TP and MM acquired, analyzed and interpreted data and statistical analysis from RNAseq. LM, DN, SK, PK and PY analyzed, interpreted data and statistical analysis of microbiota data. RR performed FISH test. EB, DL, EL and AM analyzed and interpreted data from qPCR to identification of colibactin. LL, IF and MS conducted SpiderMass analysis. GD, PS, JG, DP, CG, NB and RB acquired, analyzed and interpreted data from Clermont-Ferrand patients. DM and IS acquired, analyzed and interpreted data from Créteil. NOA wrote the manuscript and all authors discussed the results and commented on the manuscript. MC supervised the entire project.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2320291