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000296116 1001_ $$00000-0002-7912-3964$$aTorang, Arezo$$b0
000296116 245__ $$aEnterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.
000296116 260__ $$a[London]$$bNature Publishing Group UK$$c2025
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000296116 520__ $$aColorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition.
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000296116 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aProto-Oncogene Proteins p21(ras)
000296116 650_7 $$0EC 6.3.4.16$$2NLM Chemicals$$aCarbamoyl-Phosphate Synthase (Ammonia)
000296116 650_7 $$0EC 3.2.1.-$$2NLM Chemicals$$aSucrase-Isomaltase Complex
000296116 650_7 $$0K8CXK5Q32L$$2NLM Chemicals$$apyrimidine
000296116 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$aHras protein, mouse
000296116 650_7 $$2NLM Chemicals$$aPyrimidines
000296116 650_2 $$2MeSH$$aColorectal Neoplasms: genetics
000296116 650_2 $$2MeSH$$aColorectal Neoplasms: pathology
000296116 650_2 $$2MeSH$$aColorectal Neoplasms: metabolism
000296116 650_2 $$2MeSH$$aAnimals
000296116 650_2 $$2MeSH$$aEnterocytes: metabolism
000296116 650_2 $$2MeSH$$aCell Differentiation
000296116 650_2 $$2MeSH$$aHumans
000296116 650_2 $$2MeSH$$aMice
000296116 650_2 $$2MeSH$$aProto-Oncogene Proteins p21(ras): genetics
000296116 650_2 $$2MeSH$$aProto-Oncogene Proteins p21(ras): metabolism
000296116 650_2 $$2MeSH$$aOrganoids: metabolism
000296116 650_2 $$2MeSH$$aOrganoids: pathology
000296116 650_2 $$2MeSH$$aCarbamoyl-Phosphate Synthase (Ammonia): genetics
000296116 650_2 $$2MeSH$$aCarbamoyl-Phosphate Synthase (Ammonia): metabolism
000296116 650_2 $$2MeSH$$aSucrase-Isomaltase Complex: genetics
000296116 650_2 $$2MeSH$$aSucrase-Isomaltase Complex: metabolism
000296116 650_2 $$2MeSH$$aGene Expression Regulation, Neoplastic
000296116 650_2 $$2MeSH$$aCell Proliferation: genetics
000296116 650_2 $$2MeSH$$aMutation
000296116 650_2 $$2MeSH$$aCarcinogenesis: genetics
000296116 650_2 $$2MeSH$$aCell Line, Tumor
000296116 650_2 $$2MeSH$$aPyrimidines
000296116 7001_ $$aKirov, Aleksandar B$$b1
000296116 7001_ $$aLammers, Veerle$$b2
000296116 7001_ $$aCameron, Kate$$b3
000296116 7001_ $$00000-0003-4025-3531$$aWouters, Valérie M$$b4
000296116 7001_ $$0P:(DE-He78)5da14633266cbfff7746cf529c110673$$aJackstadt, Rene F$$b5$$udkfz
000296116 7001_ $$00000-0002-8206-8898$$aLannagan, Tamsin R M$$b6
000296116 7001_ $$ade Jong, Joan H$$b7
000296116 7001_ $$00000-0002-0890-7585$$aKoster, Jan$$b8
000296116 7001_ $$00000-0001-9540-3010$$aSansom, Owen$$b9
000296116 7001_ $$aMedema, Jan Paul$$b10
000296116 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-024-55574-3$$gVol. 16, no. 1, p. 264$$n1$$p264$$tNature Communications$$v16$$x2041-1723$$y2025
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