NOTUM from Apc-mutant cells biases clonal competition to initiate cancer

Show full item record



Permalink

http://hdl.handle.net/10138/337493

Citation

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 , Vincent , J-P , Katajisto , P & Sansom , O J 2021 , ' NOTUM from Apc-mutant cells biases clonal competition to initiate cancer ' , Nature , vol. 594 , no. 7863 , pp. 430-+ . https://doi.org/10.1038/s41586-021-03525-z

Title: NOTUM from Apc-mutant cells biases clonal competition to initiate cancer
Author: 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; Vincent, Jean-Paul; Katajisto, Pekka; Sansom, Owen J.
Contributor organization: Helsinki Institute of Life Science HiLIFE
Centre of Excellence in Stem Cell Metabolism
Institute of Biotechnology
University of Helsinki
Molecular and Integrative Biosciences Research Programme
Faculty of Biological and Environmental Sciences
Juha Klefström / Principal Investigator
Department of Pathology
Helsinki University Hospital Area
HUSLAB
ATG - Applied Tumor Genomics
Research Programs Unit
HUS Diagnostic Center
CAN-PRO - Translational Cancer Medicine Program
Faculty of Medicine
Kari Alitalo / Principal Investigator
Nutrient sensing laboratory
Clinicum
Date: 2021-06-17
Language: eng
Number of pages: 17
Belongs to series: Nature
ISSN: 0028-0836
DOI: https://doi.org/10.1038/s41586-021-03525-z
URI: http://hdl.handle.net/10138/337493
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 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.
Subject: STEM-CELLS
BETA-CATENIN
BONE-FORMATION
WNT
MUTATION
HOMEOSTASIS
ACTIVATION
INTESTINE
POLYPOSIS
PATHWAY
1182 Biochemistry, cell and molecular biology
3122 Cancers
Peer reviewed: Yes
Rights: other
Usage restriction: openAccess
Self-archived version: acceptedVersion


Files in this item

Total number of downloads: Loading...

Files Size Format View
Author_s_accepted_manuscript.pdf 197.1Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record