Multi-omics analyses of cancer-linked clinical salmonellae reveal bacterial-induced host metabolic shift and mTOR-dependent cell transformation

Virginie Stévenin*, Claudia E Coipan, Janneke W Duijster, Daphne M van Elsland, Linda Voogd, Lise Bigey, Angela H A M van Hoek, Lucas M Wijnands, Lennert Janssen, Jimmy J L L Akkermans, Andra Neefjes-Borst, Eelco Franz, Lapo Mughini-Gras, Jacques Neefjes*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Salmonellae are associated epidemiologically and experimentally with colon cancer. To understand how Salmonella induces cell transformation, we performed multi-omics and phenotypic analyses of Salmonella clinical strains isolated from patients later diagnosed with colon cancer (case strains) and control strains from patients without cancer. We show that high transformation efficiency is a frequent intrinsic feature of clinical (case and control) salmonellae, yet case strains showed higher transformation efficiency than control strains. Transformation efficiency correlates with gene expression, nutrient utilization, and intracellular virulence, but not with genetic features, suggesting a phenotypic convergence of Salmonella strains resulting in cell transformation. We show that both bacterial entry and intracellular replication are required for host cell transformation and are associated with hyperactivation of the mTOR pathway. Strikingly, transiently inactivating mTOR through chemical inhibition reverses the transformation phenotype instigated by Salmonella infection. This suggests that targeting the mTOR pathway could prevent the development of Salmonella-induced tumors.

Original languageEnglish
Article number114931
JournalCell Reports
Volume43
Issue number11
Early online date1 Nov 2024
DOIs
Publication statusPublished - 26 Nov 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s)

Funding

We thank Dr. Bruno Guigas and Frank Otto for their help in setting up mTOR activity detection. This work was supported by a Dutch Cancer Society KWF Kankerbestrijding grant \u201CBacterial food poisoning and colon cancer; a cell biological and epidemiological study\u201D 2017-1-11001 (to J.N., E.F., and L.M.-G.), an ERC Advanced grant ERCOPE (to J.N.), a Netherlands Organisation for Health Research and Development ZonMw grant 522004001 (to J.N., E.F., and L.M.-G.), and the Leiden University Medical Center MSCA-IF Seal of Excellence program grant SALICOCA (to V.S.). We thank Dr. Bruno Guigas and Frank Otto for their help in setting up mTOR activity detection. This work was supported by a KWF Kankerbestrijding grant \u201CBacterial food poisoning and colon cancer; a cell biological and epidemiological study\u201D 2017-1-11001 (to J.N., E.F., and L.M.-G.), an ERC Advanced grant ERCOPE (to J.N.), a Netherlands Organisation for Health Research and Development ZonMw grant 522004001 (to J.N., E.F., and L.M.-G.), and the Leiden University Medical Center MSCA-IF Seal of Excellence program SALICOCA (to V.S.).

FundersFunder number
Leids Universitair Medisch Centrum
Dutch Cancer Society KWF Kankerbestrijding
ERC Advanced grant ERCOPE
KWF Kankerbestrijding
Bacterial food poisoning and colon cancer2017-1-11001
ZonMw522004001
ZonMw

    Keywords

    • CP: Cancer
    • CP: Microbiology
    • Salmonella
    • carcinogenic bacteria
    • clinical strains
    • colon cancer
    • genomic
    • host cell transformation
    • mTOR
    • metabolism
    • transcriptomic
    • virulence

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