TGF-ß Tumor Suppression through a Lethal EMT.
Cell
; 164(5): 1015-30, 2016 Feb 25.
Article
en En
| MEDLINE
| ID: mdl-26898331
ABSTRACT
TGF-ß signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-ß mediator Smad4. We show that TGF-ß induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-ß-sensitive PDA cells, EMT becomes lethal by converting TGF-ß-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-ß. TGF-ß-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-ß tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Factor de Crecimiento Transformador beta
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Carcinoma Ductal
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Redes Reguladoras de Genes
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Transición Epitelial-Mesenquimal
Límite:
Animals
Idioma:
En
Revista:
Cell
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos