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Suppression of intestinal tumors by targeting the mitotic spindle of intestinal stem cells

Oncogene volume 35, pages 6109–6119 (2016)Cite this article

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Abstract

Human colorectal cancer is often initiated by the aberrant activation of Wnt signaling, notably following adenomatous polyposis coli (Apc) inactivation. Recent studies identified adult intestinal stem cells (ISCs) and demonstrated their role as the cells of origin for intestinal tumors. However, the early consequences of aberrant Wnt signaling activation remain to be fully elucidated. Here, using organoid cultures established from conditional knockout mice and in vitro gene ablation, we show that Apc inactivation led to aberrant ISC proliferation and the expansion of the crypt domain. This system was used to evaluate the potential of a cancer-related spindle protein, Tacc3, as a target of cancer therapy, as its disruption led to the suppression of tumor formation in an animal model of intestinal tumors. We found that Tacc3 is required for the proper mitosis of Apc-deficient ISCs, and its disruption significantly attenuated the expansion of the crypt domain. In vivo analysis of corresponding mutant mice demonstrated that Tacc3 disruption led to a significant decrease in tumor number and prolonged survival. These observations demonstrated that Tacc3 is a potential chemotherapeutic target for intestinal tumors by perturbing the aberrant cell proliferation of Apc-deficient ISCs and provides an opportunity for the development of novel cancer prevention and treatment.

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Acknowledgements

We thank Dr Tomoyuki Kitagawa for continuous support and Ms Yuki Ota for technical assistance with the microarray analysis. We also thank Dr Toshiro Sato for valuable advice on the mouse intestine organoid culture. This study is partially supported by the research program for the Project for Development of Innovative Research on Cancer Therapeutics, P-Direct from the Japan Agency for Medical Research and Development, AMED (RY), Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (RY), and The Vehicle Racing Commemorative Foundation (RY).

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Authors and Affiliations

  1. Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan

    R Yao, J Oyanagi, Y Natsume, D Kusama, Y Kato & T Noda

  2. Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan

    S Nagayama

  3. Director’s Room, Cancer Institute, Japanese Foundation for Cancer Research (JFCR), Koto-Ku, Tokyo, Japan

    T Noda

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  1. R Yao
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Correspondence to R Yao.

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Yao, R., Oyanagi, J., Natsume, Y. et al. Suppression of intestinal tumors by targeting the mitotic spindle of intestinal stem cells. Oncogene 35, 6109–6119 (2016). https://doi.org/10.1038/onc.2016.148

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  • DOI: https://doi.org/10.1038/onc.2016.148

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