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Induction of endoplasmic reticulum stress by deletion of Grp78 depletes Apc mutant intestinal epithelial stem cells

Oncogene volume 36, pages 3397–3405 (2017)Cite this article

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Abstract

Intestinal epithelial stem cells are highly sensitive to differentiation induced by endoplasmic reticulum (ER) stress. Colorectal cancer develops from mutated intestinal epithelial stem cells. The most frequent initiating mutation occurs in Apc, which results in hyperactivated Wnt signalling. This causes hyperproliferation and reduced sensitivity to chemotherapy, but whether these mutated stem cells are sensitive to ER stress induced differentiation remains unknown. Here we examined this by generating mice in which both Apc and ER stress repressor chaperone Grp78 can be conditionally deleted from the intestinal epithelium. For molecular studies, we used intestinal organoids derived from these mice. Homozygous loss of Apc alone resulted in crypt elongation, activation of the Wnt signature and accumulation of intestinal epithelial stem cells, as expected. This phenotype was however completely rescued on activation of ER stress by additional deletion of Grp78. In these Apc-Grp78 double mutant animals, stem cells were rapidly lost and repopulation occurred by non-mutant cells that had escaped recombination, suggesting that Apc-Grp78 double mutant stem cells had lost self-renewal capacity. Although in Apc-Grp78 double mutant mice the Wnt signature was lost, these intestines exhibited ubiquitous epithelial presence of nuclear β-catenin. This suggests that ER stress interferes with Wnt signalling downstream of nuclear β-catenin. In conclusion, our findings indicate that ER stress signalling results in loss of Apc mutated intestinal epithelial stem cells by interference with the Wnt signature. In contrast to many known inhibitors of Wnt signalling, ER stress acts downstream of β-catenin. Therefore, ER stress poses a promising target in colorectal cancers, which develop as a result of Wnt activating mutations.

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Acknowledgements

This work was supported by a VENI grant from the Dutch Organisation for Scientific Research (NWO) and by a research stipendium from the Dutch Cancer Foundation (KWF).

Author contributions

JFvLdJ, JH, VM, designed experiments, analysed and discussed data. JFvLdJ, BJM, MCBW, BB, SLR, YHS and SM performed the experiments. ASL provided Grp78fl/fl mice, JCP and AWP provided SubAB and SubAA272BJH, VM and GRvdB supervised the study. JFvLdJ and JH wrote the manuscript with input of all authors.

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Authors and Affiliations

  1. Tygat Institute for Liver and Intestinal Research and Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands

    J F van Lidth de Jeude, B J Meijer, M C B Wielenga, C N Spaan, B Baan, S L Rosekrans, S Meisner, Y H Shen, V Muncan, G R van den Brink & J Heijmans

  2. Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    A S Lee

  3. Department of Molecular and Cellular Biology, Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, South Australia, Australia

    J C Paton & A W Paton

  4. Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands

    J Heijmans

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  1. J F van Lidth de Jeude
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van Lidth de Jeude, J., Meijer, B., Wielenga, M. et al. Induction of endoplasmic reticulum stress by deletion of Grp78 depletes Apc mutant intestinal epithelial stem cells. Oncogene 36, 3397–3405 (2017). https://doi.org/10.1038/onc.2016.326

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