title: Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma.
abstract: Cancer is fueled by deregulation of signaling pathways in control of cellular growth and proliferation. These pathways are also targeted by infectious pathogens en route to establishing infection. Gallbladder carcinoma (GBC) is frequent in the Indian subcontinent, with chronic Salmonella enterica serovar Typhi infection reported as a significant risk factor. However, direct association and causal mechanisms between Salmonella Typhi infection and GBC have not been established. Deconstructing the epidemiological association between GBC and Salmonella Typhi infection, we show that Salmonella enterica induces malignant transformation in predisposed mice, murine gallbladder organoids, and fibroblasts, with TP53 mutations and c-MYC amplification. Mechanistically, activation of MAPK and AKT pathways, mediated by Salmonella enterica effectors secreted during infection, is critical to both ignite and sustain transformation, consistent with observations in GBC patients from India. Collectively, our findings indicate that Salmonella enterica can promote transformation of genetically predisposed cells and is a causative agent of GBC.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands. Electronic address: t.scanu@nki.nl.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Scanu
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Robbert M
authors.initials: RM
authors.lastname: Spaapen
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Jeroen M
authors.initials: JM
authors.lastname: Bakker
authors.affiliation: Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
authors.forename: Chandra Bhan
authors.initials: CB
authors.lastname: Pratap
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Lin-en
authors.initials: LE
authors.lastname: Wu
authors.affiliation: Core Facility Molecular Pathology and Biobanking, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hofland
authors.affiliation: Core Facility Molecular Pathology and Biobanking, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.affiliation: Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Shukla
authors.affiliation: Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
authors.forename: Mohan
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Janssen
authors.affiliation: Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Ji-Ying
authors.initials: JY
authors.lastname: Song
authors.affiliation: Department of Pathology, Free University Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
authors.forename: E Andra
authors.initials: EA
authors.lastname: Neefjes-Borst
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands.
authors.forename: Hein
authors.initials: H
authors.lastname: te Riele
authors.affiliation: Center for Molecular Bacteriology and Infection, Imperial College London, London SW72AZ, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Holden
authors.affiliation: Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
authors.forename: Gopal
authors.initials: G
authors.lastname: Nath
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands. Electronic address: j.neefjes@nki.nl.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000382:microbiology; D005347:Fibroblasts / Q000382:microbiology / Q000473:pathology; D005706:Gallbladder Neoplasms / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007194:India; D020935:MAP Kinase Signaling System; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009426:Netherlands; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012480:Salmonella Infections / Q000150:complications / Q000235:genetics / Q000382:microbiology / Q000473:pathology*; D019779:Salmonella enterica / Q000378:metabolism / Q000472:pathogenicity*; D012485:Salmonella typhi / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D015398:Signal Transduction
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc