Apc-mutant cells act as supercompetitors in intestinal tumour initiation
Open accessAbstract
A delicate equilibrium of WNT agonists and antagonists in the intestinal stem cell (ISC) niche is critical to maintaining the ISC compartment, as it accommodates the rapid renewal of the gut lining. Disruption of this balance by mutations in the tumour suppressor gene APC, which are found in approximately 80% of all human colon cancers, leads to unrestrained activation of the WNT pathway 1,2. It has previously been established that Apc-mutant cells have a competitive advantage over wild-type ISCs 3. Consequently, Apc-mutant ISCs frequently outcompete all wild-type stem cells within a crypt, thereby reaching clonal fixation in the tissue and initiating cancer formation. However, whether the increased relative fitness of Apc-mutant ISCs involves only cell-intrinsic features or whether Apc mutants are actively involved in the elimination of their wild-type neighbours remains unresolved. Here we show that Apc-mutant ISCs function as bona fide supercompetitors by secreting WNT antagonists, thereby inducing differentiation of neighbouring wild-type ISCs. Lithium chloride prevented the expansion of Apc-mutant clones and the formation of adenomas by rendering wild-type ISCs insensitive to WNT antagonists through downstream activation of WNT by inhibition of GSK3β. Our work suggests that boosting the fitness of healthy cells to limit the expansion of pre-malignant clones may be a powerful strategy to limit the formation of cancers in high-risk individuals.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In intestinal stem cells, Apc mutant clones secrete WNT antagonists that promote the differentiation of wild-type clones.
“A similar positive feedforward model of competitive outgrowth of mutant cells has been shown in intestinal stem cells where Apc mutant clones secrete WNT antagonists that promote the differentiation of wild-type clones [87];”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [87]
The retrieved passages labeled Abstract contain bibliographic metadata and the paper title, but no findings about WNT antagonists or wild-type cell differentiation. Searches for the claim’s wording and for NOTUM yielded no relevant passage in our copy, so the proposed mechanism cannot be verified from it. (LLM, conf=0.70)
Experimental — accuracy not yet measuredBecause Apc-mutant cells themselves are insensitive to WNT modulation, this leads to their expansion and adenoma formation.
“because Apc-mutant cells themselves are insensitive to WNT modulation, this leads to their expansion and adenoma formation.”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [87]
The indexed passages contain bibliographic metadata and the title (unlabelled and Abstract-labelled entries, no page given), but no passage about WNT modulation or the proposed cause of Apc-mutant cell expansion and adenoma formation. Searches for WNT insensitivity and for expansion and adenoma formation returned no relevant text from the paper. (LLM, conf=0.73)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890 · see citing works
Trimmomatic: a flexible trimmer for Illumina sequence data
Bolger, A. M., Lohse, M., & Usadel, B. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu170 · Cited by 65,548 · see citing works
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499 · see citing works
<i>Stan</i> : A Probabilistic Programming Language
Carpenter, B., Gelman, A., Hoffman, M. D., Lee, D., Goodrich, B., Betancourt, M., Brubaker, M., Guo, J., Li, P., & Riddell, A. (2017) · Journal of Statistical Software · doi:10.18637/jss.v076.i01 · Cited by 7,754 · see citing works
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · see citing works
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G. J., van Es, J. H., van den Brink, S., van Houdt, W. J., Pronk, A., van Gorp, J., Siersema, P. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.050 · Cited by 3,753 · see citing works
Counter, C. M., Botelho, F. M., Wang, P., Harley, C. B., & Bacchetti, S. (1994) · Journal of Virology · doi:10.1128/jvi.68.5.3410-3414.1994 · Cited by 355 · see citing works
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
Flanagan, D. J., Pentinmikko, N., Luopajärvi, K., Willis, N. J., Gilroy, K., Raven, A. P., Mcgarry, L., Englund, J. I., Webb, A. T., Scharaw, S., et al. (2021) · Nature · doi:10.1038/s41586-021-03525-z · Cited by 255 · see citing works
TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype
Fessler, E., Drost, J., van Hooff, S. R., Linnekamp, J. F., Wang, X., Jansen, M., De Sousa E Melo, F., Prasetyanti, P. R., IJspeert, J. E., Franitza, M., et al. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606184 · Cited by 159 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Joanito, I., Wirapati, P., Zhao, N., Nawaz, Z., Yeo, G., Lee, F., Eng, C. L. P., Macalinao, D. C., Kahraman, M., Srinivasan, H., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01100-4 · Cited by 434 · see citing works
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
Flanagan, D. J., Pentinmikko, N., Luopajärvi, K., Willis, N. J., Gilroy, K., Raven, A. P., Mcgarry, L., Englund, J. I., Webb, A. T., Scharaw, S., et al. (2021) · Nature · doi:10.1038/s41586-021-03525-z · Cited by 255 · see citing works
Clonal hematopoiesis and inflammation – the perpetual cycle
Avagyan, S., & Zon, L. I. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.12.001 · Cited by 79 · see citing works
Dijkstra, J. J., Neikes, H. K., Rezaeifard, S., Ma, X., Voest, E. E., Tauriello, D. V. F., & Vermeulen, M. (2023) · Journal of Proteome Research · doi:10.1021/acs.jproteome.2c00551 · Cited by 23 · see citing works
Nakai, K., Lin, H., Yamano, S., Tanaka, S., Kitamoto, S., Saitoh, H., Sakuma, K., Kurauchi, J., Akter, E., Konno, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42774-6 · Cited by 14 · see citing works
- Authors
- van Neerven, S. M., de Groot, N. E., Nijman, L. E., Scicluna, B. P., van Driel, M. S., Lecca, M. C., Warmerdam, D. O., Kakkar, V., Moreno, L. F., Vieira Braga, F. A., Sanches, D. R., Ramesh, P., ten Hoorn, S., Aelvoet, A. S., van Boxel, M. F., Koens, L., Krawczyk, P. M., Koster, J., Dekker, E., Medema, J. P., Winton, D. J., Bijlsma, M. F., Morrissey, E., Léveillé, N., & Vermeulen, L.
- Affiliations
- Oncode Institute (NL)
- Amsterdam University Medical Centers (NL)
- Amsterdam UMC Location University of Amsterdam (NL)
- University of Cambridge (GB)
- John Radcliffe Hospital (GB)
- Corresponding author
- Vermeulen, Louis
- ORCID
- van Neerven, Sanne M.
- Nijman, Lisanne E.
- Scicluna, Brendon P.
- van Driel, Milou S.
- Warmerdam, Daniël O.
- Moreno, Leandro F.
- Vieira Braga, Felipe A.
- Aelvoet, Arthur S.
- van Boxel, Marouska F.
- Koens, Lianne
- Krawczyk, Przemek M.
- Koster, Jan
- Dekker, Evelien
- Medema, Jan Paul
- Winton, Douglas J.
- Bijlsma, Maarten F.
- Morrissey, Edward
- Léveillé, Nicolas
- Vermeulen, Louis
- Venue
- Nature
- Published
- 2021-06-02
- Volume
- 594
- Issue
- 7863
- Pages
- 436-441
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3165875563
- Cited by
- 211
- References
- 9
- Citations by year
- 2026: 29 · 2025: 31 · 2024: 49 · 2023: 44 · 2022: 37 · 2021: 20
- FWCI
- 11.77
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- New York Stem Cell Foundation (ERG-StG 638193, UVA2014-7245)
- ZonMw (ERG-StG 638193, 016.156.308, UVA2014-7245, Vidi 016.156.308)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (022.005.002, Vidi 016.156.308)
- Maag Lever Darm Stichting (MLDS-CDG 14-03)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- APC mutation, intestinal stem cells, Wnt antagonists, Wnt signaling, clonal expansion, adenoma formation, GSK3β, lithium chloride, stem cell differentiation, colon cancer, organoids
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Cell Competition, Adenoma, Animals, Cell Differentiation, Female, Humans, Intestinal Neoplasms, Male, Mutation, Organoids, Genes, APC, Lithium Chloride, Adenomatous Polyposis Coli Protein, Wnt Proteins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
