Nature Communications (Jan 2024)
Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
- 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
Affiliations
- Candice R. Gurbatri
- Department of Biomedical Engineering, Columbia University
- Georgette A. Radford
- Adelaide Medical School, University of Adelaide
- Laura Vrbanac
- Adelaide Medical School, University of Adelaide
- Jongwon Im
- Department of Biomedical Engineering, Columbia University
- Elaine M. Thomas
- Adelaide Medical School, University of Adelaide
- Courtney Coker
- Department of Biomedical Engineering, Columbia University
- Samuel R. Taylor
- Weill Cornell-Rockefeller-Sloan Kettering Tri-Institutional MD-PhD program
- YoungUk Jang
- Department of Biomedical Engineering, Columbia University
- Ayelet Sivan
- Department of Biomedical Engineering, Columbia University
- Kyu Rhee
- Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medicine
- Anas A. Saleh
- Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medicine
- Tiffany Chien
- Department of Biomedical Engineering, Columbia University
- Fereshteh Zandkarimi
- Department of Chemistry, Columbia University
- Ioana Lia
- Department of Biomedical Engineering, Columbia University
- Tamsin R. M. Lannagan
- Adelaide Medical School, University of Adelaide
- Tongtong Wang
- Adelaide Medical School, University of Adelaide
- Josephine A. Wright
- South Australian Health and Medical Research Institute (SAHMRI)
- Hiroki Kobayashi
- Adelaide Medical School, University of Adelaide
- Jia Q. Ng
- Adelaide Medical School, University of Adelaide
- Matt Lawrence
- Colorectal Unit, Department of Surgery, Royal Adelaide Hospital
- Tarik Sammour
- Adelaide Medical School, University of Adelaide
- Michelle Thomas
- Colorectal Unit, Department of Surgery, Royal Adelaide Hospital
- Mark Lewis
- Colorectal Unit, Department of Surgery, Royal Adelaide Hospital
- Lito Papanicolas
- South Australian Health and Medical Research Institute (SAHMRI)
- Joanne Perry
- Colorectal Unit, Department of Surgery, Royal Adelaide Hospital
- Tracy Fitzsimmons
- Colorectal Unit, Department of Surgery, Royal Adelaide Hospital
- Patricia Kaazan
- Adelaide Medical School, University of Adelaide
- Amanda Lim
- Adelaide Medical School, University of Adelaide
- Alexandra M. Stavropoulos
- Adelaide Medical School, University of Adelaide
- Dion A. Gouskos
- Adelaide Medical School, University of Adelaide
- Julie Marker
- Cancer Voices SA
- Cheri Ostroff
- University of South Australia
- Geraint Rogers
- South Australian Health and Medical Research Institute (SAHMRI)
- Nicholas Arpaia
- Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University
- Daniel L. Worthley
- South Australian Health and Medical Research Institute (SAHMRI)
- Susan L. Woods
- Adelaide Medical School, University of Adelaide
- Tal Danino
- Department of Biomedical Engineering, Columbia University
- DOI
- https://doi.org/10.1038/s41467-024-44776-4
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 13
Abstract
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.
