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1.
Nature ; 594(7863): 430-435, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34079124

RESUMO

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.


Assuntos
Competição entre as Células , Transformação Celular Neoplásica , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Esterases/metabolismo , Genes APC , Mutação , Adenoma/genética , Adenoma/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Competição entre as Células/genética , Diferenciação Celular , Proliferação de Células , Transformação Celular Neoplásica/genética , Meios de Cultivo Condicionados , Progressão da Doença , Esterases/antagonistas & inibidores , Esterases/genética , Feminino , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Organoides/citologia , Organoides/metabolismo , Organoides/patologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
2.
Gastroenterology ; 159(1): 183-199, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32179094

RESUMO

BACKGROUND & AIMS: Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice. METHODS: We generated mice with IEC-specific disruption of Mcl1 (Mcl1ΔIEC mice) or tamoxifen-inducible IEC-specific disruption of Mcl1 (i-Mcl1ΔIEC mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces. RESULTS: Mcl1ΔIEC mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1ΔIEC mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1ΔIEC mice reduced markers of microbiota-induced intestinal inflammation but not tumor development. CONCLUSION: The antiapoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1ΔIEC mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases.


Assuntos
Carcinoma/patologia , Mucosa Intestinal/patologia , Neoplasias Intestinais/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Animais , Apoptose/genética , Apoptose/imunologia , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Carcinoma/diagnóstico , Carcinoma/genética , Modelos Animais de Doenças , Endoscopia , Células Epiteliais/patologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/diagnóstico por imagem , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/genética , Camundongos , Camundongos Transgênicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética
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