Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma
Typhoid bacteria can push already-damaged gallbladder cells into becoming cancerous: in mice, gallbladder organoids and cells with faulty TP53 and extra MYC, Salmonella infection switched on growth signalling that started and maintained the transformation.
Overview
Gallbladder carcinoma is frequent in the Indian subcontinent, where chronic Salmonella enterica serovar Typhi infection is a reported risk factor, but a causal mechanism had not been established. Deconstructing the epidemiological association, the authors showed that Salmonella enterica induces malignant transformation in predisposed mice, murine gallbladder organoids and fibroblasts carrying TP53 mutations and c-MYC amplification.
Mechanistically, activation of MAPK and AKT pathways, mediated by Salmonella effectors secreted during infection, was critical both to ignite and to sustain transformation, consistent with observations in gallbladder cancer patients from India. The findings indicate that Salmonella enterica can promote transformation of genetically predisposed cells and is a causative agent of gallbladder carcinoma.
- Salmonella enterica transformed predisposed (TP53-mutant, c-MYC-amplified) mouse cells, gallbladder organoids and fibroblasts.
- Bacterial effectors activated MAPK and AKT signalling, required to start and sustain transformation.
- Findings were consistent with tumours from Indian patients.
A mechanism for the oldest epidemiological clue in gallbladder cancer, and a reason the disease appears so early in India. It frames typhoid control and cholecystectomy in chronic carriers as cancer prevention, and MAPK and AKT as pathways worth watching in infection-associated tumours.
- Mouse and organoid work; the human evidence is epidemiological and immunohistochemical.
- Predisposing mutations were engineered, so the sequence of events in patients is inferred.
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