Pentinmikko N

References (2)

Title : NOTUM from Apc-mutant cells biases clonal competition to initiate cancer - Flanagan_2021_Nature__
Author(s) : Flanagan DJ , Pentinmikko N , Luopajarvi K , Willis NJ , Gilroy K , Raven AP , McGarry L , Englund JI , Webb AT , Scharaw S , Nasreddin N , Hodder MC , Ridgway RA , Minnee E , Sphyris N , Gilchrist E , Najumudeen AK , Romagnolo B , Perret C , Williams AC , Clevers H , Nummela P , Lahde M , Alitalo K , Hietakangas V , Hedley A , Clark W , Nixon C , Kirschner K , Jones EY , Ristimaki A , Leedham SJ , Fish PV , Vincent JP , Katajisto P , Sansom OJ
Ref : Nature , : , 2021
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.
ESTHER : Flanagan_2021_Nature__
PubMedSearch : Flanagan_2021_Nature__
PubMedID: 34079124
Gene_locus related to this paper: human-NOTUM

Title : Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium - Pentinmikko_2019_Nature_571_398
Author(s) : Pentinmikko N , Iqbal S , Mana M , Andersson S , Cognetta AB, 3rd , Suciu RM , Roper J , Luopajarvi K , Markelin E , Gopalakrishnan S , Smolander OP , Naranjo S , Saarinen T , Juuti A , Pietilainen K , Auvinen P , Ristimaki A , Gupta N , Tammela T , Jacks T , Sabatini DM , Cravatt BF , Yilmaz OH , Katajisto P
Ref : Nature , 571 :398 , 2019
Abstract : A decline in stem cell function impairs tissue regeneration during ageing, but the role of the stem-cell-supporting niche in ageing is not well understood. The small intestine is maintained by actively cycling intestinal stem cells that are regulated by the Paneth cell niche(1,2). Here we show that the regenerative potential of human and mouse intestinal epithelium diminishes with age owing to defects in both stem cells and their niche. The functional decline was caused by a decrease in stemness-maintaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth cells. Mechanistically, high activity of mammalian target of rapamycin complex 1 (mTORC1) in aged Paneth cells inhibits activity of peroxisome proliferator activated receptor alpha (PPAR-alpha)(3), and lowered PPAR-alpha activity increased Notum expression. Genetic targeting of Notum or Wnt supplementation restored function of aged intestinal organoids. Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged stem cells and promoted recovery from chemotherapy-induced damage. Our results reveal a role of the stem cell niche in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.
ESTHER : Pentinmikko_2019_Nature_571_398
PubMedSearch : Pentinmikko_2019_Nature_571_398
PubMedID: 31292548
Gene_locus related to this paper: human-NOTUM , mouse-notum