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

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.