مورد إلكتروني
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
| العنوان: | NOTUM from Apc-mutant cells biases clonal competition to initiate cancer |
|---|---|
| المصدر: | Nature vol.594 (2021) nr.7863 p.430-435 [ISSN 0028-0836] |
| بيانات النشر: | 2021 |
| تفاصيل مُضافة: | Flanagan, Dustin J Pentinmikko, Nalle Luopajärvi, Kalle Willis, Nicky J Gilroy, Kathryn Raven, Alexander P Mcgarry, Lynn Englund, Johanna I Webb, Anna T Scharaw, Sandra Nasreddin, Nadia Hodder, Michael C Ridgway, Rachel A Minnee, Emma Sphyris, Nathalie Gilchrist, Ella Najumudeen, Arafath K Romagnolo, Beatrice Perret, Christine Williams, Ann C Clevers, Hans Nummela, Pirjo Lähde, Marianne Alitalo, Kari Hietakangas, Ville Hedley, Ann Clark, William Nixon, Colin Kirschner, Kristina Jones, E Yvonne Ristimäki, Ari Leedham, Simon J Fish, Paul V Vincent, Jean-Paul Katajisto, Pekka Sansom, Owen J |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | 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. |
| مصطلحات الفهرس: | Adenoma/genetics, Adenomatous Polyposis Coli Protein/genetics, Animals, Cell Competition/genetics, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic/genetics, Colorectal Neoplasms/genetics, Culture Media, Conditioned, Disease Progression, Esterases/antagonists & inhibitors, Female, Genes, APC, Humans, Ligands, Male, Mice, Mice, Inbred C57BL, Mutation, Organoids/cytology, Stem Cells/cytology, Wnt Proteins/metabolism, Wnt Signaling Pathway, Artikel, Article |
| URL: | |
| الإتاحة: | Open access content. Open access content info:eu-repo/semantics/openAccess |
| ملاحظة: | DOI: 10.1038/s41586-021-03525-z Nature vol.594 (2021) nr.7863 p.430-435 [ISSN 0028-0836] English |
| أرقام أخرى: | NLKNA oai:pure.knaw.nl:publications/69a3582f-fc29-4f40-bc5f-17ba7825a11a https://pure.knaw.nl/portal/en/publications/69a3582f-fc29-4f40-bc5f-17ba7825a11a 1295315657 |
| المصدر المساهم: | KON NED AKADEMIE VAN WETENSCHAPPEN From OAIster®, provided by the OCLC Cooperative. |
| رقم الأكسشن: | edsoai.on1295315657 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |