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NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
Open accessAbstract
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 signalling 1, 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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“both S45P and D32G showed upregulation of Notum, a negative Wnt regulator previously shown to promote cell competition in APC-deficient colorectal cancer cells41.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [41]
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Self-citation
Metadata
- Authors
- 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., Nasreddin, N., Hodder, M. C., Ridgway, R. A., Minnee, E., Sphyris, N., Gilchrist, E., Najumudeen, A. K., Romagnolo, B., Perret, C., Williams, A. C., Clevers, H., Nummela, P., Lähde, M., Alitalo, K., Hietakangas, V., Hedley, A., Clark, W., Nixon, C., Kirschner, K., Jones, E. Y., Ristimäki, A., Leedham, S. J., Fish, P. V., Vincent, J.-P., Katajisto, P., & Sansom, O. J.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- University of Helsinki (FI)
- Alzheimer’s Research UK (GB)
- Harvard University (US)
- Karolinska Institutet (SE)
- Centre for Human Genetics (GB)
- Centre National de la Recherche Scientifique (FR)
- University of Bristol (GB)
- Royal Netherlands Academy of Arts and Sciences (NL)
- University of Glasgow (GB)
- The Francis Crick Institute (GB)
- Corresponding author
- Katajisto, Pekka
- Sansom, Owen J.
- ORCID
- Flanagan, Dustin J.
- Pentinmikko, Nalle
- Willis, Nicky J.
- Gilroy, Kathryn
- Raven, Alexander P.
- Mcgarry, Lynn
- Englund, Johanna I.
- Webb, Anna T.
- Scharaw, Sandra
- Nasreddin, Nadia
- Ridgway, Rachel A.
- Sphyris, Nathalie
- Gilchrist, Ella
- Najumudeen, Arafath K.
- Perret, Christine
- Williams, Ann C.
- Clevers, Hans
- Nummela, Pirjo
- Alitalo, Kari
- Hietakangas, Ville
- Hedley, Ann
- Clark, William
- Nixon, Colin
- Kirschner, Kristina
- Jones, E. Yvonne
- Leedham, Simon J.
- Fish, Paul V.
- Vincent, Jean-Paul
- Katajisto, Pekka
- Sansom, Owen J.
- Venue
- Nature
- Published
- 2021-06-02
- Volume
- 594
- Issue
- 7863
- Pages
- 430-435
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7615049
- OpenAlex
- W3165366231
- Cited by
- 255
- References
- 35
- Citations by year
- 2026: 40 · 2025: 43 · 2024: 49 · 2023: 57 · 2022: 43 · 2021: 22
- FWCI
- 13.81
- Type
- journal article
- Language
- en
- Open access
- green
- pure.knaw.nl
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion)
- Explore Bristol Research (submittedVersion, other-oa)
- Funders
- Wellcome Trust (FC001002, FC001204, 206314/Z/17/Z, 206341/Z/17/Z)
- Francis Crick Institute (10204)
- Cancer Research UK (27144, S_4098, 17721, FC001204, 21139)
- Medical Research Council (MR/R017247/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- notum, APC mutation, colorectal cancer, clonal competition, mutation fixation, Wnt signaling, Wnt antagonists, intestinal stem cells, intestinal adenoma, organoids, tumour suppressor, colorectal cancer prevention
- MeSH terms
- Cell Competition, Adenoma, Animals, Cell Differentiation, Cell Transformation, Neoplastic, Esterases, Female, Humans, Ligands, Male, Mice, Inbred C57BL, Mutation, Organoids, Stem Cells, Colorectal Neoplasms, Culture Media, Conditioned, Genes, APC, Disease Progression, Adenomatous Polyposis Coli Protein, Cell Proliferation, Wnt Proteins, Mice, Wnt Signaling Pathway
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