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Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche

Abstract

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

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Figure 1: Human HMPS polyps.
Figure 2: Vil1-Grem1 mouse phenotype.
Figure 3: Gene expression analysis of separated villus compartments in Vil1-Grem1 mice.
Figure 4: In vitro villus cell clonogenicity.
Figure 5: Effect of Grem1 on conventional Wnt-driven tumorigenesis and pathogenic role in human sporadic TSAs.
Figure 6: Model summarizing the proposed mechanistic consequences of disrupted GREM1 morphogen gradients.

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Acknowledgements

This work was funded by Cancer Research UK Clinician Scientist Fellowship A16581 to S.J.L. and Programme grant A16459 to I.T. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). We thank the transgenics core and the staff of the Functional Genomics Facility at the Wellcome Trust Centre for Human Genetics. Villin-MES-SV40polyA plasmid was a kind gift from S. Robine (Institut Curie, Paris, France).

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Authors and Affiliations

Authors

Contributions

S.J.L. and I.T. conceived and designed the project. Experiments were conducted by H.D., S.I., H.R., T.B., C.B., E.J., A.L., P.R.-C. and S.J.L. In situ hybridization was completed by H.D., R.J., R.P. and A.S. Bioinformatic analysis carried out by S.I., M.B., L.F.-M. and F.C.G. Pathology support, tissue provision and intellectual input were provided by S.M., S.C., H.T., M.R.-J., M.N., R.C., L.M.W. and J.E.E. Mouse resources were supplied by O.J.S. and F.R.G. The manuscript was written by S.J.L. and I.T.

Corresponding authors

Correspondence to Ian Tomlinson or Simon J Leedham.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 5721 kb)

Supplementary Table 1

VSN-filtered normalized gene expression data from mouse wild-type and Vill-Grem1 small intestinal villi (XLSX 3901 kb)

Supplementary Table 2

Differentially expressed probes between Vill-Grem1 mouse small intestinal villi versus wild-type mouse villi (XLSX 5763 kb)

Supplementary Table 3

List of a priori gene signatures used in interrogating gene expression data from villi of Vill-Grem1 mice using Gene Set Enrichment Analysis (XLSX 58 kb)

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Davis, H., Irshad, S., Bansal, M. et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat Med 21, 62–70 (2015). https://doi.org/10.1038/nm.3750

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