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An innovative gall bladder organoid model provides mechanistic insights into the link between Salmonella Paratyphi A infection and gall bladder cancer.

Gall bladder cancer is the most common cancer of the biliary system and is unfortunately associated with very poor outcomes. Although this cancer is rare in Western countries, there is relatively high prevalence in the northern part of the Indian subcontinent and western regions of South America. In these regions, there is an epidemiological association between gall bladder cancer and chronic infection with the bacteria Salmonella enterica Typhi/Paratyphi A but the mechanistic basis for this correlation is unknown.

To investigate this, Ludwig Oxford’s Dr Francesco Boccellato and colleagues from Professor Thomas Meyer’s laboratory at the Max Planck Institute for Infection Biology, Berlin, developed a long-lived 3D organoid model that recapitulates the infection dynamics in the healthy gallbladder epithelium. As observed previously, infection with Salmonella induced DNA double-strand breaks that were dependent on the typhoid toxin CdtB subunit produced by the bacteria. With their advanced organoid model, they were able to see the toxin and DNA damage spread to neighbouring cells that were not infected with Salmonella. Of particular interest, infected cells underwent a toxin-independent cell cycle arrest. By contrast, uninfected intoxicated cells were able to continue proliferating despite the DNA damage, providing a potential opportunity for malignant transformation.

This work, published in the journal mBio, provides the mechanistic basis to put Salmonella enterica Typhi/Paratyphi A on the list of cancer-causing pathogens along with other more well-known examples such as Helicobacter pylori and highlights the importance of studying bacterial toxins to understand cancer initiation. Long term intoxication might represent a risk factor for cancer development and identification of other relevant toxin-producing bacteria is an urgent issue to understand more prevalent cancers like colon, bladder and cancers of the genital tract, where bacterial infection might play an under-recognised role.

 

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