Abstract
Although the Wnt/β-catenin pathway plays a central role in the carcinogenesis and maintenance of colorectal cancer (CRC), attempts to target the pathway itself have not been very successful. MyD88, an adaptor protein of the TLR/IL-1β signaling, has been implicated in the integrity of the intestines as well as in their tumorigenesis. In this study, we aimed to clarify the mechanisms by which epithelial MyD88 contributes to intestinal tumor formation and to address whether MyD88 can be a therapeutic target of CRC. Conditional knockout of MyD88 in intestinal epithelial cells (IECs) reduced tumor formation in Apc+/Δ716 mice, accompanied by decreased proliferation and enhanced apoptosis of tumor epithelial cells. Mechanistically, the MyD88 loss caused inactivation of the JNK-mTORC1, NF-κB, and Wnt/β-catenin pathways in tumor cells. Induction of MyD88 knockout in the intestinal tumor-derived organoids, but not in the normal IEC-derived organoids, induced apoptosis and reduced their growth. Treatment with the MyD88 inhibitor ST2825 also suppressed the growth of the intestinal tumor-derived organoids. Knockdown of MYD88 in human CRC cell lines with mutations in APC or CTNNB1 induced apoptosis and reduced their proliferation as well. These results indicate that MyD88 loss is synthetic lethal with mutational activation of the Wnt/β-catenin signaling in intestinal tumor epithelial cells. Inhibition of MyD88 signaling can thus be a novel therapeutic strategy for familial adenomatous polyposis (FAP) as well as for colorectal cancer harboring mutations in the Wnt/β-catenin signaling.
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Acknowledgements
We would like to thank Dr Thaddeus S. Stappenbeck and Dr Hiroyuki Miyoshi for kindly giving us L-WRN cells, Yumiko Ito for technical assistance, and Dr Ayako Demachi-Okamura for technical advice.
Funding
This work was supported by JSPS Grant-in-Aid for Scientific Research (JP18K07254) to RKS and JSPS Grant-in-Aid for Scientific Research on Innovative Areas (JP26111001) to MA.
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Kajino-Sakamoto, R., Fujishita, T., Taketo, M.M. et al. Synthetic lethality between MyD88 loss and mutations in Wnt/β-catenin pathway in intestinal tumor epithelial cells. Oncogene 40, 408–420 (2021). https://doi.org/10.1038/s41388-020-01541-3
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DOI: https://doi.org/10.1038/s41388-020-01541-3