A Bioluminescent transposon reporter-trap identifi es tumor-specifi c microenvironment-induced promoters in salmonella for conditional bacterial-based tumor therapy

Kelly Flentie, Brandon Kocher, Seth T. Gammon, Deborah V. Novack, Jeffrey S. McKinney, David Piwnica-Worms

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Salmonella specifi cally localize to malignant tumors in vivo, a trait potentially exploitable as a delivery system for cancer therapeutics. To characterize mechanisms and genetic responses of Salmonella during interaction with living neoplastic cells, we custom-designed a promoterless transposon reporter containing bacterial luciferase. Analysis of a library containing 7,400 independent Salmonella transposon insertion mutants in coculture with melanoma or colon carcinoma cells identifi ed fi ve bacterial genes specifi cally activated by cancer cells: adiY, yohJ, STM1787, STM1791, and STM1793. Experiments linked acidic pH, a common characteristic of the tumor microenvironment, to a strong, specifi c, and reversible stimulus for activation of these Salmonella genes in vitro and in vivo. Indeed, a Salmonella reporter strain encoding a luciferase transgene regulated by the STM1787 promoter, which contains a tusp motif, showed tumor-induced bioluminescence in vivo. Furthermore, Salmonella expressing Shiga toxin from the STM1787 promoter provided potent and selective antitumor activity in vitro and in vivo, showing the potential for a conditional bacterial-based tumor-specifi c therapeutic. SIGNIFICANCE: Salmonella, which often encounter acidic environments during classical host infection, may co-opt evolutionarily conserved pathways for tumor colonization in response to the acidic tumor microenvironment. We identifi ed specifi c promoter sequences that provide a platform for targeted Salmonella-based tumor therapy in vivo.

Original languageEnglish (US)
Pages (from-to)624-637
Number of pages14
JournalCancer Discovery
Volume2
Issue number7
DOIs
StatePublished - Jul 2012

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Salmonella
Neoplasms
Tumor Microenvironment
Therapeutics
Bacterial Luciferases
Shiga Toxin
Bacterial Genes
Coculture Techniques
Luciferases
Transgenes
Transcriptional Activation
Libraries
Melanoma
Colon
Carcinoma
Infection

ASJC Scopus subject areas

  • Oncology

Cite this

A Bioluminescent transposon reporter-trap identifi es tumor-specifi c microenvironment-induced promoters in salmonella for conditional bacterial-based tumor therapy. / Flentie, Kelly; Kocher, Brandon; Gammon, Seth T.; Novack, Deborah V.; McKinney, Jeffrey S.; Piwnica-Worms, David.

In: Cancer Discovery, Vol. 2, No. 7, 07.2012, p. 624-637.

Research output: Contribution to journalArticle

Flentie, Kelly ; Kocher, Brandon ; Gammon, Seth T. ; Novack, Deborah V. ; McKinney, Jeffrey S. ; Piwnica-Worms, David. / A Bioluminescent transposon reporter-trap identifi es tumor-specifi c microenvironment-induced promoters in salmonella for conditional bacterial-based tumor therapy. In: Cancer Discovery. 2012 ; Vol. 2, No. 7. pp. 624-637.
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