Abstract
The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.
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Data availability
The RNA sequencing data generated in this study are publicly available through the Gene Expression Omnibus (GEO) with the accession code GSE167008. All other data are available from the corresponding authors on reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196 and A31287), and particularly the Biological Services Unit, Histology Service and Molecular Technologies; members of the Sansom and Katajisto laboratories for discussions of the data and manuscript; and BRC Oxford for supplying patient material. O.J.S. and his laboratory members were supported by Cancer Research UK (A28223, A21139, A12481 and A17196). D.J.F. and M.C.H. were supported by the UK Medical Research Council (MR/R017247/1 and MR/J50032X/1, respectively). SpecifiCancer CRUK Grand Challenge (C7932/A29055) is funded by Cancer Research UK and the Mark Foundation for Cancer Research. P.K. and his laboratory members were supported by the Academy of Finland Centre of Excellence MetaStem (266869, 304591 and 320185), the ERC Starting Grant 677809, the Swedish Research Council 2018-03078, the Cancerfonden 190634, the Jane and Aatos Erkko Foundation and the Cancer Foundation Finland. N.P. was supported by the Finnish Cultural Foundation, the Biomedicum Helsinki Foundation, the Orion Research Foundation sr and The Paulo Foundation. P.V.F. was supported by Alzheimer’s Research UK and The Francis Crick Institute. The ARUK UCL Drug Discovery Institute receives its core funding from Alzheimer’s Research UK (520909). The Francis Crick Institute receives its core funding from Cancer Research UK (FC001002), the UK Medical Research Council (FC001002) and the Wellcome Trust (FC001002).
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D.J.F., N.P., P.K. and O.J.S. designed and interpreted the results of all experiments. D.J.F., N.P., K.L., A.P.R., L.M., J.I.E., A.T.W., S.S., N.N., E.G., E.M., M.C.H. and R.A.R. performed all of the experiments and analysed the results. D.J.F. performed and analysed the organoid experiments. K.G., K.K., A.H. and W.C. processed and analysed the RNA sequencing data. C.N. performed ISH. N.S. provided advice on manuscript preparation. A.K.N., N.J.W., B.R., C.P., A.C.W., H.C., P.V.F., P.N., M.L., V.H., K.A., A.R., S.J.L., E.Y.J. and J.-P.V. provided advice and reagents. D.J.F., N.S., N.P., P.K. and O.J.S. wrote the paper.
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Extended data figures and tables
Extended Data Fig. 1 Notum secreted by Apc-mutant clones inhibits WT organoid growth.
a, Volcano plot of significantly differentially expressed Wnt-target genes in Apc-mutant (VilCreER;Apcfl/+) tumour tissue compared to WT small intestine (n = 3 WT mice, n = 5 VilCreER;Apcfl/+ mice). This is the same data set as in Fig. 1a but with different Wnt-target genes highlighted (green dots) using Wald test (two-tailed). b, Notum-ISH shows high levels of Notum expression in the intestine of multiple Wnt-driven tumour models of the indicated genotypes (Ctnnb1Ex3/+, 30 days; Apc1322T/+, 98 days; ApcMin/+, 125 days). Sections from n = 4 mice per genotype were stained. Scale bar, 200 μm. c, ISH of serial en face sections of intestinal tissue from Lgr5CreER;Apcfl/fl mice 10 days after tamoxifen induction. BaseScope ISH for recombined Apc (ApcEx14-ISH) and Notum (Notum-ISH) shows exclusive expression of Notum in cells that have recombined Apc (cells lacking pink RNA dots in right panel). The boxed areas show a close-up of Notum+ Apc-mutant crypts, demarcated by a dashed line. Sections from n = 4 mice per genotype were stained. Scale bar, 20 μm. d, Notum-ISH timecourse (days 6, 28, 60 and >100) after tamoxifen induction in Lgr5CreER;Apcfl/fl mice shows specific Notum expression in progressively dysplastic epithelium. Sections from n = 4 mice per genotype were stained. Scale bar, 100 μm. e, Quantification of the number of crypt domains per WT organoid following indicated treatments. Each data point represents a single mouse; n = 6 mice. f, Relative WT organoid viability measured at passage 3 following treatments as indicated. n = 5 mice per condition. g, Schematic illustrating the mouse breeding scheme to generate Lgr5CreER;Apcfl/fl;Notumfl/fl mice for treatment of WT organoids with Apc−/−;Notum−/− CM (Apc−/−;Notum−/− CM) (top). Representative images of WT organoids grown in Apc−/−;Notum−/− CM for 5 days and supplemented with recombinant NOTUM (bottom). Treatments were repeated twice on WT organoids derived from n = 3 mice. Scale bar, 200 μm. Data are mean ± s.e.m. In e, f, Mann–Whitney two-tailed U-test; P values are shown in the corresponding panels.
Extended Data Fig. 2 Apc-mutant cells upregulate negative regulators of Wnt signalling.
a, Raw sequence reads for transcripts encoding Wnt-negative regulators, Wif1 and Dkk3, in Apc-mutant (VilCreER;Apcfl/+) tumour tissue compared to WT small intestine (n = 3 WT mice, n = 5 VilCreER;Apcfl/+mice). b, Representative ISH for Wif1 and Dkk3 in Lgr5CreER;Apcfl/fl tumour (top panels) and WT small intestine (bottom panels). n = 3 mice. Images of mice shown aged 3–4 months. The boxed areas show close-ups of WT crypts. Scale bar, 200 μm. c, Quantification and representative images of WT organoids, formed over multiple passages (P1, P2 and P3), during culture supplemented with recombinant WIF1, DKK3 and NOTUM. WT organoids treated with recombinant proteins were derived from n = 3 mice. Images taken at P2. Mann–Whitney one-tailed U-test. Scale bar, 200 μm. d, Quantitative PCR (qPCR) for Wnt antagonists expressed by tamoxifen-induced Lgr5CreER;Apcfl/fl (Notum+/+) and Lgr5CreER;Apcfl/fl;Notumfl/fl (Notumfl/fl) small intestinal organoids. n = 4 mice per genotype. e, qPCR for Wnt targets expressed in WT organoids 3 days following treatment with indicated recombinant Wnt antagonists. n = 3 mice per treatment. Mann–Whitney one-tailed U-test. f, Quantification of VilCreER;Apcfl/fl organoids 3 days after culture with recombinant WIF1, DKK3 and NOTUM. n = 3 mice per condition. g, Relative organoid viability and representative images of VilCreER;Apcfl/fl intestinal organoids treated with vehicle or NOTUMi for 3 days. n = 3 mice/condition. Scale bar, 100 μm. Data are mean ± s.e.m. In d, Mann–Whitney two-tailed U-test; P values are shown in the corresponding panels.
Extended Data Fig. 3 Notum is required for Apc-mutant cells to form intestinal tumours.
a, Survival plot for Lgr5CreER;Apcfl/fl;Notum+/+ (Notum+/+) and Lgr5CreER;Apcfl/fl;Notumfl/fl (Notumfl/fl) mice aged until clinical end point following induction with 0.15 mg tamoxifen. (n = 10 Notum+/+ mice, n = 10 Notumfl/fl mice). P = 0.12, log-rank test. b, Total small intestinal tumour burden (area) per mouse from mice in a (n = 10 Notum+/+ mice, n = 9 Notumfl/fl mice). c, Small intestinal tumour number per mouse from mice in a (n = 10 Notum+/+ mice, n = 10 Notumfl/fl mice). d, Representative H&E and Notum-ISH staining on serial sections from Notum+/+ and Notumfl/fl mice in a. The asterisks denote intestinal adenomas. The boxed areas are close-ups of adenomas stained for Notum. Note that adenomas grow out as Notum-positive lesions in Notumfl/fl mice, suggesting that retaining Notum confers a survival advantage during adenoma development. Scale bars, 200 μm. Data are mean ± s.e.m. In, b, c, Mann–Whitney U-test; P values are shown in the corresponding panels.
Extended Data Fig. 4 Generation and characterization of novel Notum conditional knockout.
a, Schematic of the Notum locus and recombined Notumc allele with relevant genome editing sites indicated. b, Southern blot analysis of embryonic stem (ES) cell Notumc clones and WT genomic DNA showing successful recombination at the Notum locus (4.7-kb product). The 13.6-band and 4.7-kb band represent endogenous and recombined alleles, respectively (arrows). c, Schematic of tamoxifen treatment regimen and tissue analysis 7 and 14 d.p.i. of Lgr5CreER;Apcfl/fl;Notum+/+ (NotumWT) and Lgr5CreER;Apcfl/fl;Notumc/c (NotumcKO) mice (top). Representative images of small intestinal sections stained for β-catenin from NotumWT and NotumcKO mice 14 days following induction with 120 mg/kg (3 mg) tamoxifen are also shown (bottom). The arrows indicate dysplastic crypts with nuclear β-catenin (magenta border). The boxed area shows a close-up of β-catenin+ crypts. Sections from n = 4 mice per genotype were stained. Scale bar, 50 μm. d, Representative agarose gel electrophoresis of products from conventional PCR showing relative recombination of Apcfl and Notumc alleles 5 days after tamoxifen induction. The 250-bp and 513-bp bands represent recombined Apc and Notum, respectively. For gel source data, see Supplementary Fig. 2. n = 3 mice. e, Quantification of small intestinal β-catenin+ lesions in NotumWT and NotumcKO mice, induced with 3 mg tamoxifen, and sampled at 7 and 14 d.p.i. n = 4 per genotype at 7 d.p.i; n = 18 NotumWT mice and n = 12 NotumcKO mice at 14 d.p.i. f, Quantification of large intestinal β-catenin+ lesions at 14 d.p.i (n = 18 NotumWT mice, n = 12 NotumcKO mice). g, Representative images of β-catenin IHC depicting fully and partially fixed Apc-mutant crypts in NotumWT and NotumcKO mice, respectively (left). Mice were induced with 3 mg tamoxifen and sampled at 14 d.p.i (n = 4 per genotype). The ratio of fully to partially fixed crypts in NotumWT and NotumcKO mice is also shown (right). Scale bar, 100 μm. h, Relative percentages of clonal crypt classification (clonal crypt phenotype) from mice described in g. i, Analysis of NotumWT and NotumcKO adenomas at 14 d.p.i. Representative confocal images (left). Ki67 (magenta), Lgr5–EGFP (green), nuclei (cyan), β-catenin (white) and adenomas (yellow dashed line). Quantification of Lgr5+ cell frequency within β-catenin+ Apc-mutant clones (middle). Proliferation of Lgr5+ and Lgr5− Apc-mutant cells (β-catenin+) (right). n = 5 mice/genotype. Scale bar, 20 μm. In the box plots, the line represents the median, the box shows the interquartile range and the whiskers represent the range. Data are mean ± s.e.m. In e–g, i, Mann–Whitney two-tailed U-test; P values are shown in the corresponding panels.
Extended Data Fig. 5 Deletion of Notum does not disrupt intestinal homeostasis.
a, Schematic of the tamoxifen (TMX) treatment regimen and analysis of tissues from Lgr5CreER;Notumc/c mice (top). Representative agarose gel electrophoresis of products from conventional PCR detecting alleles for non-recombined and recombined Notumc (238 and 513 bp, respectively) in Lgr5hi cells isolated from Lgr5CreER;Notumc/c mice with or without tamoxifen induction (bottom). Cells were isolated from n = 3 mice/genotype per time point. b, H&E staining of WT (NotumWT) and NotumcKO tissue collected 8 months after tamoxifen induction. The right panels show regular crypt-villus architecture in both cohorts. Sections from n = 4 mice per genotype were stained. Scale bar, 5 mm. c, Cellular frequencies of crypt cells, analysed by flow cytometry, remain unchanged after Notum deletion (WT, n = 5; NotumcKO, n = 6). ISCs (Lgr5hi), transit-amplifying cells (Lgr5med and Lgr5lo), Paneth cells and enteroendocrine cells (Endo). For FACS gating strategy, see Supplementary Fig. 1. In the box plots, the line represents the median, the box shows the interquartile range and the whiskers represent the range. d, Representative images and quantification of organoid regeneration (shown as the number of crypt domains per organoid) of WT and NotumcKO (cKO) organoid cultures, (WT, n = 3; NotumcKO, n = 4). Scale bar, 100 μm. e, Clonogenic growth of isolated Lgr5hi cells is increased in NotumcKO (cKO) compared to WT. Colonies were quantified 7 days post-seeding; n = 3 independent organoid lines per genotype. Mann–Whitney one-tailed U-test. Scale bar, 100 μm. Data are mean ± s.e.m. In d, Mann–Whitney two-tailed U-test; P values are shown in the corresponding panels. Representative images taken at day 6 (d) and day 7 (e) of culture. For gel source data, see Supplementary Fig. 1.
Extended Data Fig. 6 Notum drives the elimination of WT cells from the crypt independent of apoptosis.
a, Quantification and representative confocal imaging of cleaved caspase-3+ cells (CC3) within clonal crypts and the surrounding non-mutant epithelium in NotumWT and NotumcKO mice at 14 d.p.i. n = 4 per genotype. Crypts adjacent (Adj.) to or remote (Rem.) from Apc-mutant (clone) crypts were scored as non-mutant epithelia. The red arrows indicate CC3+ cells (green) in areas of Apc-mutant clones (purple border) and surrounding epithelia. Scale bar, 50 μm. Data are mean ± s.e.m.; Mann–Whitney two-tailed U-test.
Extended Data Fig. 7 Cells that escape Notum deletion upregulate Wif1, but not Dkk3.
a, Quantification of the relative percentage of Notum+ adenomas (as detected via Notum-ISH) in VilCreER;ApcMin/+;Notum+/+ (+/+) and VilCreER;ApcMin/+;Notumfl/fl (fl/fl) mice aged 85 days. Mice were induced with 2 mg tamoxifen at 6 and 8 weeks of age. n = 11 Notum+/+ and n = 8 Notumfl/fl mice. b, Representative RFP-IHC of VilCreER;ApcMin/+;tdTom+ tumour tissue to show recombination efficiency at 85 days of age. Mice were induced with 2 mg tamoxifen at 6 and 8 weeks of age. The boxed area shows a close-up of recombined (dark brown cells) and non-recombined (light brown cells) tumour epithelium from a single VilCreER;ApcMin/+;tdTom+ mouse. Sections from n = 4 mice were stained. Scale bar, 10 mm. c, Serial sections of intestinal tumour tissue stained via ISH for Notum, Wif1 and Dkk3 from two separate VilCreER;ApcMin/+;Notumfl/fl mice described in a. Note, Wif1 is upregulated in Notum-negative epithelial cells (boxed area). Scale bar, 50 μm. Data are mean ± s.e.m.
Extended Data Fig. 8 Notum is expressed by ligand-independent and not ligand-dependent tumours.
a, Relative percentages of clonal crypt classification (clonal crypt phenotype) from Lgr5CreER;Apcfl/fl mice induced with 0.15 mg tamoxifen followed by twice-daily treatment with vehicle or NOTUMi (30 mg/kg) and sampled 21 days post-induction. n = 4 mice per treatment group. b, Quantification of β-catenin+ lesions from mice described in a. c, Representative examples of high, moderate and low NOTUM expression (as shown via ISH) within human colonic adenoma tissue. The arrows indicate single NOTUM-positive cells. Staining was performed on more than 10 patient samples. Scale bar, 20 μm. d, Representative NOTUM expression, as shown by fluorescent ISH (FISH) on human colonic adenoma tissue. Of note, NOTUM expression is minimally expressed in known RSPO1 fusion mutant adenoma tissue (traditional serrated adenoma (TSA)). Staining was performed on more than 10 patient samples. Scale bar, 50 μm. TVA, tubulovillous adenoma. e, Representative Notum-ISH and β-catenin-IHC on VilCreER;Rnf43fl/fl;Znrf3fl/fl mice 14 d.p.i. (2 mg tamoxifen). The boxed areas show close-ups of nuclear β-catenin+/Notum− epithelium (right panels). Sections from n = 4 mice per genotype were stained. Scale bar, 50 μm. f, Quantification and representative images of WT organoids treated for 5 days with CM collected from VilCreER;Rnf43fl/fl;Znrf3fl/fl organoids (R/Z−/− CM) ± recombinant NOTUM. R/Z−/− CM was collected from organoids derived from n = 3 mice. WT organoids treated with CM ± NOTUM were derived from n = 3 mice. Treatments were repeated twice. Mann–Whitney one-tailed U-test. Scale bar, 100 μm. Data are mean ± s.e.m. In b, Mann–Whitney two-tailed U-test; P values are shown in the corresponding panels.
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This file includes Supplementary Figures 1-2 which contain the FACS gating strategy (Supplementary Fig. 1) and the uncropped scans of gel electrophoresis (Supplementary Fig. 2).
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Flanagan, D.J., Pentinmikko, N., Luopajärvi, K. et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature 594, 430–435 (2021). https://doi.org/10.1038/s41586-021-03525-z
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DOI: https://doi.org/10.1038/s41586-021-03525-z
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