ATDC is required for the initiation of KRAS-induced pancreatic tumorigenesis.
Genes Dev
; 33(11-12): 641-655, 2019 06 01.
Article
em En
| MEDLINE
| ID: mdl-31048544
ABSTRACT
Pancreatic adenocarcinoma (PDA) is an aggressive disease driven by oncogenic KRAS and characterized by late diagnosis and therapeutic resistance. Here we show that deletion of the ataxia-telangiectasia group D-complementing (Atdc) gene, whose human homolog is up-regulated in the majority of pancreatic adenocarcinoma, completely prevents PDA development in the context of oncogenic KRAS. ATDC is required for KRAS-driven acinar-ductal metaplasia (ADM) and its progression to pancreatic intraepithelial neoplasia (PanIN). As a result, mice lacking ATDC are protected from developing PDA. Mechanistically, we show ATDC promotes ADM progression to PanIN through activation of ß-catenin signaling and subsequent SOX9 up-regulation. These results provide new insight into PDA initiation and reveal ATDC as a potential target for preventing early tumor-initiating events.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Fatores de Transcrição
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Proteínas Proto-Oncogênicas p21(ras)
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Carcinoma Ductal Pancreático
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Carcinogênese
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article