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

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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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Correspondence to Sumaira Hasnain or Michael A. McGuckin.

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Ethical approval is obtained from University of Queensland Animal Ethics Committee.

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