A genome‑wide screen in E. coli reveals metabolic adaptations that enhance intratumoral fitness and bacterial cancer therapy efficacy
(1) Chen N (2) Rouanne M (3) Yang Z (4) Mariuzza DL (5) Fabozzi M (6) Shin AE (7) Nishiwaki N (8) Rajbhandari P (9) Ringham OR (10) Schwabe AD (11) Zhu M (12) Stockwell BR (13) Mori H (14) Danino T (15) Arpaia N
Utilizing a high-throughput barcoded KO screen targeting all non-essential E. coli genes, Chen et al. identified that KO of non-glucose phosphotransferase system genes enhanced intratumoral fitness and tumor colonization by increasing glucose avidity. A quadruple-mutant, tumor-avid E. coli strain (Ec-TA) outcompeted and displaced wild-type E. coli from pre-colonized tumors, demonstrated tumor specificity and a favorable safety profile, and increased delivery of an IFNγ payload upon intravenous administration. Ec-TA-IFNγ enhanced intratumoral IFNγ and effector T cell responses, and reduced tumor burden across colorectal tumor models.
Contributed by Ute Burkhardt
(1) Chen N (2) Rouanne M (3) Yang Z (4) Mariuzza DL (5) Fabozzi M (6) Shin AE (7) Nishiwaki N (8) Rajbhandari P (9) Ringham OR (10) Schwabe AD (11) Zhu M (12) Stockwell BR (13) Mori H (14) Danino T (15) Arpaia N
Utilizing a high-throughput barcoded KO screen targeting all non-essential E. coli genes, Chen et al. identified that KO of non-glucose phosphotransferase system genes enhanced intratumoral fitness and tumor colonization by increasing glucose avidity. A quadruple-mutant, tumor-avid E. coli strain (Ec-TA) outcompeted and displaced wild-type E. coli from pre-colonized tumors, demonstrated tumor specificity and a favorable safety profile, and increased delivery of an IFNγ payload upon intravenous administration. Ec-TA-IFNγ enhanced intratumoral IFNγ and effector T cell responses, and reduced tumor burden across colorectal tumor models.
Contributed by Ute Burkhardt
ABSTRACT: Despite decades of investigation, the fundamental molecular and cellular principles that enable bacteria to thrive within the tumor microenvironment have yet to be defined. Here, through a genome‑wide functional screen, we identify the bacterial genes and pathways that govern intratumoral fitness. Targeted deletion of nonglucose phosphotransferase systems to align bacterial metabolic preference with tumor metabolite availability promotes bacterial intratumoral fitness. Integrating multiple metabolic adaptations into a single tumor‑avid Escherichia coli strain (Ec‑TA) results in increased tumor colonization, not only after intratumoral delivery but also after intravenous delivery, leading to increased anti‑tumor efficacy when using Ec‑TA engineered to deliver an encoded immunostimulatory payload. Furthermore, Ec‑TA displaces wild‑type bacteria from pre‑colonized tumors when administered systemically, underscoring its potential for locally delivering therapeutics in the presence of resident tumor microbes. These data demonstrate that adapting bacteria to the unique characteristics of the tumor metabolic microenvironment can drive the development of safer and more effective chassis for next‑generation bacterial cancer therapies.
Author Info:
(1) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbi
a University, New York, NY, USA. (2) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. (3) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (4) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (5) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (6) Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (7) Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (8) Department of Biological Sciences, Columbia University, New York, NY, USA. (9) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. (10) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (11) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. (12) Department of Biological Sciences, Department of Chemistry, and Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Irving Institute for Cancer Dynamics, Digestive and Liver Disease Research Center, Columbia University, New York, NY, USA. (13) Department of Environmental Science and Technology, Faculty of Engineering, Shinshu University, Nagano, Japan. (14) Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. Department of Biomedical Engineering, Columbia University, New York, NY, USA. Data Science Institute, Columbia University, New York, NY, USA. (15) Department of Microbiology & Immunology, Columbia University, New York, NY, USA. na2697@cumc.columbia.edu. Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA. na2697@cumc.columbia.edu.
