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Bacterial cancer therapy (BCT) shows great promise for treatment of solid tumors, yet basic mechanisms of bacterial-induced tumor suppression remain undefined. Attenuated strains of Salmonella enterica serovar Typhimurium (STm) have commonly been used in mouse models of BCT in xenograft and orthotopic transplant cancer models. We aimed to better understand the tumor epithelium-targeted mechanisms of BCT by using autochthonous mouse models of intestinal cancer and tumor organoid cultures to assess the effectiveness and consequences of oral treatment with aromatase A-deficient STm (STmΔaroA). STmΔaroA delivered by oral gavage significantly reduced tumor burden and tumor load in both a colitis-associated colorectal cancer (CAC) model and in a spontaneous Apcmin/+ intestinal cancer model. STmΔaroA colonization of tumors caused alterations in transcription of mRNAs associated with tumor stemness, epithelialmesenchymal transition, and cell cycle. Metabolomic analysis of tumors demonstrated alteration in the metabolic environment of STmΔaroA-treated tumors, suggesting that STmΔaroA imposes metabolic competition on the tumor. Use of tumor organoid cultures in vitro recapitulated effects seen on tumor stemness, mesenchymal markers, and altered metabolome. Furthermore, live STmΔaroA was required, demonstrating active mechanisms including metabolite usage. We have demonstrated that oral BCT is efficacious in autochthonous intestinal cancer models, that BCT imposes metabolic competition, and that BCT has direct effects on the tumor epithelium affecting tumor stem cells.
The authors thank David Bending, Adam Cunningham, Jeff Cole, and Nobuo Sasaki for critical reading of the manuscript and suggestions; Sophia Begum and Lisa Scarfe for technical assistance; Calvin Kuo for providing R-spoI producing cells; and Hidenori Matsui for UF20 STm. KMM was supported by a RIKEN Programs for Young Scientists Foreign Postdoctoral Researcher Fellowship and is currently supported by a CRUK CEA (C61638/A27112). The Japan Society for the Promotion of Science KAKENHI (19H01030) and Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (J15652274), awarded to H Ohno, also supported the work.
- Colorectal cancer
- Bacterial infections
ASJC Scopus subject areas
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1/04/19 → 31/03/25