Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
Abstract Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine m...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-44776-4 |
| _version_ | 1827377170472763392 |
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| author | Candice R. Gurbatri Georgette A. Radford Laura Vrbanac Jongwon Im Elaine M. Thomas Courtney Coker Samuel R. Taylor YoungUk Jang Ayelet Sivan Kyu Rhee Anas A. Saleh Tiffany Chien Fereshteh Zandkarimi Ioana Lia Tamsin R. M. Lannagan Tongtong Wang Josephine A. Wright Hiroki Kobayashi Jia Q. Ng Matt Lawrence Tarik Sammour Michelle Thomas Mark Lewis Lito Papanicolas Joanne Perry Tracy Fitzsimmons Patricia Kaazan Amanda Lim Alexandra M. Stavropoulos Dion A. Gouskos Julie Marker Cheri Ostroff Geraint Rogers Nicholas Arpaia Daniel L. Worthley Susan L. Woods Tal Danino |
| author_facet | Candice R. Gurbatri Georgette A. Radford Laura Vrbanac Jongwon Im Elaine M. Thomas Courtney Coker Samuel R. Taylor YoungUk Jang Ayelet Sivan Kyu Rhee Anas A. Saleh Tiffany Chien Fereshteh Zandkarimi Ioana Lia Tamsin R. M. Lannagan Tongtong Wang Josephine A. Wright Hiroki Kobayashi Jia Q. Ng Matt Lawrence Tarik Sammour Michelle Thomas Mark Lewis Lito Papanicolas Joanne Perry Tracy Fitzsimmons Patricia Kaazan Amanda Lim Alexandra M. Stavropoulos Dion A. Gouskos Julie Marker Cheri Ostroff Geraint Rogers Nicholas Arpaia Daniel L. Worthley Susan L. Woods Tal Danino |
| author_sort | Candice R. Gurbatri |
| collection | DOAJ |
| description | Abstract Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules. |
| first_indexed | 2024-03-08T12:36:08Z |
| format | Article |
| id | doaj.art-16a3783ebc994816bc3440bb05df9c6f |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T12:36:08Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-16a3783ebc994816bc3440bb05df9c6f2024-01-21T12:27:29ZengNature PortfolioNature Communications2041-17232024-01-0115111310.1038/s41467-024-44776-4Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasiaCandice R. Gurbatri0Georgette A. Radford1Laura Vrbanac2Jongwon Im3Elaine M. Thomas4Courtney Coker5Samuel R. Taylor6YoungUk Jang7Ayelet Sivan8Kyu Rhee9Anas A. Saleh10Tiffany Chien11Fereshteh Zandkarimi12Ioana Lia13Tamsin R. M. Lannagan14Tongtong Wang15Josephine A. Wright16Hiroki Kobayashi17Jia Q. Ng18Matt Lawrence19Tarik Sammour20Michelle Thomas21Mark Lewis22Lito Papanicolas23Joanne Perry24Tracy Fitzsimmons25Patricia Kaazan26Amanda Lim27Alexandra M. Stavropoulos28Dion A. Gouskos29Julie Marker30Cheri Ostroff31Geraint Rogers32Nicholas Arpaia33Daniel L. Worthley34Susan L. Woods35Tal Danino36Department of Biomedical Engineering, Columbia UniversityAdelaide Medical School, University of AdelaideAdelaide Medical School, University of AdelaideDepartment of Biomedical Engineering, Columbia UniversityAdelaide Medical School, University of AdelaideDepartment of Biomedical Engineering, Columbia UniversityWeill Cornell-Rockefeller-Sloan Kettering Tri-Institutional MD-PhD programDepartment of Biomedical Engineering, Columbia UniversityDepartment of Biomedical Engineering, Columbia UniversityDivision of Infectious Diseases, Weill Department of Medicine, Weill Cornell MedicineDivision of Infectious Diseases, Weill Department of Medicine, Weill Cornell MedicineDepartment of Biomedical Engineering, Columbia UniversityDepartment of Chemistry, Columbia UniversityDepartment of Biomedical Engineering, Columbia UniversityAdelaide Medical School, University of AdelaideAdelaide Medical School, University of AdelaideSouth Australian Health and Medical Research Institute (SAHMRI)Adelaide Medical School, University of AdelaideAdelaide Medical School, University of AdelaideColorectal Unit, Department of Surgery, Royal Adelaide HospitalAdelaide Medical School, University of AdelaideColorectal Unit, Department of Surgery, Royal Adelaide HospitalColorectal Unit, Department of Surgery, Royal Adelaide HospitalSouth Australian Health and Medical Research Institute (SAHMRI)Colorectal Unit, Department of Surgery, Royal Adelaide HospitalColorectal Unit, Department of Surgery, Royal Adelaide HospitalAdelaide Medical School, University of AdelaideAdelaide Medical School, University of AdelaideAdelaide Medical School, University of AdelaideAdelaide Medical School, University of AdelaideCancer Voices SAUniversity of South AustraliaSouth Australian Health and Medical Research Institute (SAHMRI)Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia UniversitySouth Australian Health and Medical Research Institute (SAHMRI)Adelaide Medical School, University of AdelaideDepartment of Biomedical Engineering, Columbia UniversityAbstract Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.https://doi.org/10.1038/s41467-024-44776-4 |
| spellingShingle | Candice R. Gurbatri Georgette A. Radford Laura Vrbanac Jongwon Im Elaine M. Thomas Courtney Coker Samuel R. Taylor YoungUk Jang Ayelet Sivan Kyu Rhee Anas A. Saleh Tiffany Chien Fereshteh Zandkarimi Ioana Lia Tamsin R. M. Lannagan Tongtong Wang Josephine A. Wright Hiroki Kobayashi Jia Q. Ng Matt Lawrence Tarik Sammour Michelle Thomas Mark Lewis Lito Papanicolas Joanne Perry Tracy Fitzsimmons Patricia Kaazan Amanda Lim Alexandra M. Stavropoulos Dion A. Gouskos Julie Marker Cheri Ostroff Geraint Rogers Nicholas Arpaia Daniel L. Worthley Susan L. Woods Tal Danino Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia Nature Communications |
| title | Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia |
| title_full | Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia |
| title_fullStr | Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia |
| title_full_unstemmed | Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia |
| title_short | Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia |
| title_sort | engineering tumor colonizing e coli nissle 1917 for detection and treatment of colorectal neoplasia |
| url | https://doi.org/10.1038/s41467-024-44776-4 |
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