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TGF-β Tumor Suppression Through A Lethal EMT

ABSTRACT: TGF-β is a major tumor suppressor in gastrointestinal (GI) and squamous carcinomas, which exhibit frequent genetic inactivation of Smad4, a key TGF-β signaling component. Apoptosis is implicated as an important mediator of the tumor suppressive function of TGF-β, although this process remains poorly understood. To address this long-standing question, we dissected the tumor suppressive action of TGF-β in naïve pancreatic ductal adenocarcinoma (PDA) cells. Here we show that TGF-β/Smad4 signaling triggers an EMT in Kras-mutant pancreatic progenitor cells but turns this process into a trigger of apoptosis by converting the progenitor cell transcription factor Sox4 from an enforcer of epithelial progenitor identity into an activator of apoptosis. This occurs as a result of the EMT-linked repression of the endodermal master regulator Klf5, which cooperates with Sox4 to promote epithelial progenitor identity, and loss of which unmasks a latent apoptotic transcriptional program driven by Sox4. By losing Smad4, Kras-mutant PDA cells avoid this fate and instead use Sox4 as a TGF-β-dependent enforcer of the epithelial progenitor cell state.

ORGANISM(S): Mus musculus

PROVIDER: GSE72069 | GEO | 2016/02/24

SECONDARY ACCESSION(S): PRJNA292864

REPOSITORIES: GEO

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Project description:Deregulation of the transforming growth factor-? (TGF?) signaling pathway in epithelial ovarian cancer has been reported, but the precise mechanism underlying disrupted TGF? signaling in the disease remains unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate genome-wide screening of TGF?-induced SMAD4 binding in epithelial ovarian cancer. Following TGF? stimulation of the A2780 epithelial ovarian cancer cell line, we identified 2,362 SMAD4 binding loci and 318 differentially expressed SMAD4 target genes. Comprehensive examination of SMAD4-bound loci, revealed four distinct binding patterns: 1) Basal; 2) Shift; 3) Stimulated Only; 4) Unstimulated Only. SMAD4-bound loci were primarily classified as either Stimulated only (74%) or Shift (25%), indicating that TGF?-stimulation alters SMAD4 binding patterns in epithelial ovarian cancer cells compared to normal epithelial cells. Furthermore, based on gene regulatory network analysis, we determined that the TGF?-induced SMAD4-dependent regulatory network was strikingly different in ovarian cancer compared to normal cells. Importantly, the TGF?/SMAD4 target genes identified in the A2780 epithelial ovarian cancer cell line were predictive of patient survival, based on in silico mining of publically available patient data bases. In conclusion, our data highlight the utility of next generation sequencing technology to identify genome-wide SMAD4 target genes in epithelial ovarian cancer. The results link aberrant TGF?/SMAD signaling to ovarian tumorigenesis. Furthermore, the identified SMAD4 binding loci, combined with gene expression profiling and in silico data mining of patient cohorts, may provide a powerful approach to determine potential gene signatures with biological and future translational research in ovarian and other cancers. ChIP-Seq: 1 control lane. 4 unstimulated lanes 4 stimulated lanes Gene expression: 3 technical replicates each of SMAD4 stimulated and SMAD4 unstimulated cells

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TGF-β Tumor Suppression Through A Lethal EMT

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