Rescuing chemotaxis of the anticancer agent Salmonella enterica serovar Typhimurium VNP20009

Broadway, Katherine M.; Denson, Elizabeth A.P.; Jensen, Roderick V.; Scharf, Birgit E.

doi:10.1016/j.jbiotec.2015.07.010

Cited by 17 publications

(21 citation statements)

References 34 publications

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“…Typhimurium VNP20009 has been previously reported to exhibit preferential tumor colonization and dosage-related safety in a variety of tumor-infected animals including monkeys, pigs, and mice, as well as, humans [12, 17, 31]. The recently constructed VNP20009 derivative with restored bacterial chemotaxis, VNP20009 cheY + , has yet to be assessed in vivo for tumor colonizing ability [24]. We therefore evaluated the effects of intravenously (i.v.)…”

Section: Resultsmentioning

confidence: 99%

“…However, chemotaxis had no significant influence after 2 days for strain SL1344 [23]. VNP20009 was recently discovered to be deficient in chemotaxis, due to a non-synonymous SNP in the gene encoding the chemotaxis two component response regulator, cheY [24]. Upon replacing the deficient copy of cheY with the wild-type copy, chemotaxis was recovered to 70% of the parental strain [24].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Salmonella enterica serovar Typhimurium VNP20009 and VNP20009 with restored chemotaxis on 4T1 mouse mammary carcinoma progression

et al. 2017

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A variety of bacterial strains have been evaluated as bio-therapeutic and immunomodulatory agents to treat cancer. One such strain, Salmonella enterica serovar Typhimurium VNP20009, which is attenuated by a purine auxotrophic mutation and modified lipid A, is characterized in previous models as a safely administered, tumor colonizing agent. However, earlier work tended to use less aggressive cancer cell lines and immunocompromised animal models. Here, we investigated the safety and efficacy of VNP20009 in a highly malignant murine model of human breast cancer. Additionally, as VNP20009 has recently been found to have a defective chemotaxis system, we tested whether restoring chemotaxis would improve anti-cancer properties in this model system. Exposure to VNP20009 had no significant effect on primary mammary tumor size or pulmonary metastasis, and the tumor colonizing process appeared chemotaxis independent. Moreover, tumor-bearing mice exposed to Salmonella exhibited increased morbidity that was associated with significant liver disease. Our results suggest that VNP20009 may not be safe or efficacious when used in aggressive, metastatic breast cancer models utilizing immunocompetent animals.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Salmonella enterica serovar Typhimurium VNP20009 and VNP20009 with restored chemotaxis on 4T1 mouse mammary carcinoma progression

et al. 2017

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“…Previously, we established that the anticancer agent VNP20009 is deficient in chemotaxis, due to a SNP in cheY, the gene coding for the response regulator in the two component chemotaxis system. Upon replacing the mutated copy of cheY with the 14028 parental copy, chemotaxis was restored to almost 70%, determined using traditional capillary assays (Broadway et al, 2015). Here, we explored several factors to explain the remaining differences in chemotaxis between VNP20009 and the parental strain, including swimming speed, flagellation, attractant sensitivity, and the contribution of msbB and Suwwan deletion to the remaining defect.…”

Section: Discussionmentioning

confidence: 99%

“…VNP20009 was recently discovered to be deficient in chemotaxis, due to a non-synonymous single nucleotide polymorphism (SNP) in the gene encoding the chemotaxis two-component response regulator, cheY (Broadway et al, 2015). Upon replacing the deficient copy of cheY with the wild-type copy, chemotaxis was recovered to 70% of the parental strain (Broadway et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Upon replacing the deficient copy of cheY with the wild-type copy, chemotaxis was recovered to 70% of the parental strain (Broadway et al, 2015). The overall objective of this study was to determine if chemotaxis of VNP2009 can be optimized to enable future analysis of maximal tumor targeting potentially through positive chemotaxis to metabolic byproducts of cancerous tissue.…”

Section: Introductionmentioning

confidence: 99%

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Optimizing the restored chemotactic behavior of anticancer agent Salmonella enterica serovar Typhimurium VNP20009

Broadway

Suh

Behkam

et al. 2017

Journal of Biotechnology

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A B S T R A C TBacteria, including strains of Salmonella, have been researched and applied as therapeutic cancer agents for centuries. Salmonella are particularly of interest due to their facultative anaerobic nature, facilitating colonization of differentially oxygenated tumor regions. Additionally, Salmonella can be manipulated with relative ease, resulting in the ability to attenuate the pathogen or engineer vectors for drug delivery. It was recently discovered that the anti-cancer Salmonella enterica serovar Typhimurium strain VNP20009 is lacking in chemotactic ability, due to a non-synonymous single nucleotide polymorphism in cheY. Replacing the mutated copy of cheY with the wild-type sequence restored chemotaxis to 70% of the parental strain. We aimed to investigate further if chemotaxis of VNP20009 can be optimized. By restoring the gene msbB in VNP20009 cheY + , which confers attenuation by lipid A modification, we observed a 9% increase in swimming speed, 13% increase in swim plate performance, 19% increase in microfluidic device partitioning towards the attractant at the optimum concentration gradient, and mitigation of a non-motile cell subpopulation. We conclude that chemotaxis can be enhanced further but at the cost of changing one defining characteristic of VNP20009. A less compromised strain might be needed to employ for investigating bacterial chemotaxis in tumor interactions.

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The immunogenic potential of bacterial flagella for Salmonella‐mediated tumor therapy

Felgner

Spöring

Pawar

et al. 2020

Intl Journal of Cancer

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Genetically engineered Salmonella Typhimurium are potent vectors for prophylactic and therapeutic measures against pathogens as well as cancer. This is based on the potent adjuvanticity that supports strong immune responses. The physiology of Salmonella is well understood. It simplifies engineering of both enhanced immune-stimulatory properties as well as safety features, thus, resulting in an appropriate balance between attenuation and efficacy for clinical applications. A major virulence factor of Salmonella is the flagellum. It is also a strong pathogen-associated molecular pattern recognized by extracellular and intracellular receptors of immune cells of the host. At the same time, it represents a serious metabolic burden. Accordingly, the bacteria evolved tight regulatory mechanisms that control flagella synthesis in vivo. Here, we systematically investigated the immunogenicity and adjuvant properties of various flagella mutants of Salmonella in vitro and in a mouse cancer model in vivo. We found that mutants lacking the flagellum-specific ATPase FliHIJ or the inner membrane ring FliF displayed the greatest stimulatory capacity and strongest antitumor effects, while remaining safe in vivo. Scanning electron microscopy revealed the presence of outer membrane vesicles in the ΔfliF and ΔfliHIJ mutants. Finally, the combination of the ΔfliF and ΔfliHIJ mutations with our previously described attenuated and immunogenic background strain SF102 displayed strong efficacy against the highly resistant cancer cell line RenCa. We thus conclude that manipulating flagella biosynthesis has great potential for the construction of highly efficacious and versatile Salmonella vector strains.S.W. and M.E. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

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Rescuing chemotaxis of the anticancer agent Salmonella enterica serovar Typhimurium VNP20009

Cited by 17 publications

References 34 publications

Effect of Salmonella enterica serovar Typhimurium VNP20009 and VNP20009 with restored chemotaxis on 4T1 mouse mammary carcinoma progression

Effect of Salmonella enterica serovar Typhimurium VNP20009 and VNP20009 with restored chemotaxis on 4T1 mouse mammary carcinoma progression

Optimizing the restored chemotactic behavior of anticancer agent Salmonella enterica serovar Typhimurium VNP20009

The immunogenic potential of bacterial flagella for Salmonella‐mediated tumor therapy

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