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MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity

Oncogene volume 38, pages 7294–7310 (2019)Cite this article

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Abstract

Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103+ dendritic cells and CD8+ T lymphocytes, fewer myeloid-derived suppressor cells, and are rendered sensitive to checkpoint inhibitor immunotherapy (anti-PD-L1). Mechanistically, we show that MUC13 protects β-catenin from degradation, by interacting with GSK-3β, which increases β-catenin nuclear translocation and promotes its signaling, thereby driving cancer initiation, progression, invasion, and immune suppression. Therefore, MUC13 is a potential marker of poor prognosis in colorectal cancer, and inhibiting MUC13 may be useful in the treatment of colitis-associated cancer and sensitizing tumors to immunotherapy.

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Acknowledgements

We thank A/Prof. Allison Pettit for providing the IHC reagents. We also thank Dr Saba Farnaghi and Ms Rhea Menon for help with mice experiments. We also recognize the technical assistance of the TRI core facilities for histology, flow cytometry, and microscopy.

Author contributions

YS designed and performed experiments and wrote the paper. KW provided intellectual input to the experimental design and performed experiments. IS and AW provided intellectual input to the paper and performed survival analysis. RW and YH provided intellectual input to the paper and performed experiments. MP performed experiments. RL scored the MUC13 IHC staining. VS, RG, CN, and AP performed experiments. JH, GK, TF, and JB provided intellectual input to the experimental design and paper. KJR provided intellectual input to the project, and detailed comments and suggestions on drafts of the paper. SH and MM supervised the project and provided intellectual input to the paper.

Funding

Supported by NHMRC project grant 1060698 and funding by the Mater Foundation, MAM was supported by an NHMRC Principal Research Fellowship. RL was partly supported by a Betty McGrath/Mater Practitioner Research Fellowship. IS is supported by a QUT Vice-Chancellor’s Senior Research Fellowship. The Translational Research Institute (TRI) is supported by a grant from the Australian Government.

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Author notes

  1. These authors contributed equally: Sumaira Hasnain, Michael A. McGuckin

Authors and Affiliations

  1. Inflammatory Disease Biology and Therapeutics Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia

    Yong hua Sheng, Kuan Yau Wong, Inge Seim, Ran Wang, Maya Patrick, Rohan Lourie, Choa Ping Ng, Amirali Popat, Sumaira Hasnain & Michael A. McGuckin

  2. Comparative and Endocrine Biology Laboratory, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Brisbane, QLD, 4012, Australia

    Inge Seim

  3. Ghrelin Research Group, Translational Research Institute, Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Brisbane, QLD, 4102, Australia

    Inge Seim

  4. Integrative Biology Laboratory, College of Life Sciences, Nanjing Normal University, 210023, Nanjing, China

    Inge Seim

  5. Cancer Biology Group, Mater Research Institute, University of Queensland, Woolloongabba, Brisbane, QLD, 4101, Australia

    Yaowu He & John Hooper

  6. Bones and Immunology Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia

    Andy Wu

  7. Inflammatory Bowel Diseases Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia

    Rohan Lourie, Veronika Schreiber, Rabina Giri, Timothy H. Florin & Jakob Begun

  8. School of Pharmacy, The University of Queensland, Brisbane, QLD, 4072, Australia

    Amirali Popat

  9. Immune Profiling & Cancer Group, Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4102, Australia

    Gregor Kijanka

  10. Cancer Immunotherapies Group, Mater Research Institute, University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, 4101, Australia

    Kristen J. Radford

  11. Faculty of Medicine Dentistry and Health Sciences, University of Melbourne, Parkville, Melbourne, VIC, 3010, Australia

    Michael A. McGuckin

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  1. Yong hua Sheng
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Sheng, Y.h., Wong, K.Y., Seim, I. et al. MUC13 promotes the development of colitis-associated colorectal tumors via β-catenin activity. Oncogene 38, 7294–7310 (2019). https://doi.org/10.1038/s41388-019-0951-y

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