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Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention

Nature Biomedical Engineeringvolume 2pages2737 (2018) | Download Citation

Abstract

Chemoprevention—the use of medication to prevent cancer—can be augmented by the consumption of produce enriched with natural metabolites. However, chemopreventive metabolites are typically inactive and have low bioavailability and poor host absorption. Here, we show that engineered commensal microbes can prevent carcinogenesis and promote the regression of colorectal cancer through a cruciferous vegetable diet. The engineered commensal Escherichia coli bound specifically to the heparan sulphate proteoglycan on colorectal cancer cells and secreted the enzyme myrosinase to transform host-ingested glucosinolates—natural components of cruciferous vegetables—to sulphoraphane, an organic small molecule with known anticancer activity. The engineered microbes coupled with glucosinolates resulted in >95% proliferation inhibition of murine, human and colorectal adenocarcinoma cell lines in vitro. We also show that murine models of colorectal carcinoma fed with the engineered microbes and the cruciferous vegetable diet displayed significant tumour regression and reduced tumour occurrence.

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Acknowledgements

We thank P. Han for comments on the manuscript. This work was supported by the Agency for Science, Technology and Research (A*STAR) of Singapore (112 177 0040), Synthetic Biology Initiative of the National University of Singapore (DPRT/943/09/14), Summit Research Program of the National University Health System (NUHSRO/2016/053/SRP/05) and US Defense Threat Reduction Agency (HDTRA1-13-0037). We recognize the administrative contributions of C. Chang, I. Y. Hwang, H. L. Pham, B. E. D. Buenaflor, S. J. David and A. Seok Ting to the pre-clinical study.

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Affiliations

  1. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    • Chun Loong Ho
    • , Koon Jiew Chua
    • , Aram Kang
    • , Wen Shan Yew
    • , Jean Paul Thiery
    •  & Matthew Wook Chang
  2. NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), Life Sciences Institute, National University of Singapore, Singapore, Singapore

    • Chun Loong Ho
    • , Koon Jiew Chua
    • , Aram Kang
    • , Wen Shan Yew
    • , Yung Seng Lee
    • , Jean Paul Thiery
    •  & Matthew Wook Chang
  3. Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore

    • Hui Qing Tan
    •  & Khoon Lin Ling
  4. Department of Pathology, Singapore General Hospital, Singapore, Singapore

    • Kiat Hon Lim
  5. Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    • Yung Seng Lee

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Contributions

C.L.H., A.K. and M.W.C. designed the study. C.L.H. performed the experiments. C.L.H., H.Q.T., K.H.L. and K.L.L. conducted the animal model experiments. C.L.H. and K.J.C. contributed to the microscopic images. C.L.H., J.P.T., W.S.Y., Y.S.L. and M.W.C. analysed the data. C.L.H. and M.W.C. wrote the manuscript. M.W.C. supervised the project. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Matthew Wook Chang.

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DOI

https://doi.org/10.1038/s41551-017-0181-y