Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
20 Jan 2024

Historique:

received: 14 03 2023

accepted: 05 01 2024

medline: 21 1 2024

pubmed: 21 1 2024

entrez: 20 1 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-44776-4 PMID: 38245513

pubmed: 38245513

doi: 10.1038/s41467-024-44776-4

pii: 10.1038/s41467-024-44776-4

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

646

Subventions

Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)

ID : R01CA24916

Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)

ID : U01CA247573

Informations de copyright

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