BMP7 Signaling in TGFb Receptor-2 deficient Stromal Cells Provokes Epithelial Carcinogenesis
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ABSTRACT:
PROVIDER: PRJNA416879 | ENA |
REPOSITORIES: ENA
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Project description:Deregulated transforming growth factor-β (TGFβ) signaling is a common feature of many epithelial cancers. Deletion of TGFβ receptor type 2 (TGFBR2) in fibroblast specific protein-1 (FSP1)-positive stromal cells induces squamous cell carcinoma in the murine forestomach, implicating fibroblast-derived hepatocyte growth factor (HGF) as the major driver of the epithelium carcinogenesis. Prior to cancer development, hyperproliferative FSP1+ fibroblasts lacking TGFBR2 accumulate in the forestomach, disrupting the regulatory signaling cross-talk with the forestomach epithelium. Here, concurrent loss in TGFBR2 and SMAD4 completely abrogates the development of forestomach cancer. Bone morphogenic protein-7 (BMP7) was highly upregulated in forestomach cancer tissue, activating Smad1/5/8 signaling, cell proliferation, and HGF production in TGFBR2-deficient FSP1+ fibroblasts. This stimulation by BMP7 was lost in the combined TGFBR2 and SMAD4 double knockout fibroblasts, which included a profound decrease in HGF expression. Thus, Smad4-mediated signaling is required to initiate epithelial carcinogenesis subsequent to TGFBR2 deletion in FSP1+ fibroblasts.Implications: These findings reveal a complex cross-talk between epithelial cells and the stroma, wherein Smad4 is required to elicit squamous cell carcinomas in the forestomach of mice with TGFBR2-deficient stromal cells. Mol Cancer Res; 16(10); 1568-78. ©2018 AACR.
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Project description:Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of growth factors. They are known for their roles in regulation of osteogenesis and developmental processes and, in recent years, evidence has accumulated of their crucial functions in tumor biology. BMP7, in particular, has been implicated in breast cancer. However, little is known about BMP target genes in the context of tumor. We therefore explored the effects of BMP7 treatment on global gene transcription in five breast cancer cell lines during a 6-point time series. Data analysis included hierarchical clustering of differentially expressed genes, gene ontology enrichment analyses and model based clustering of temporal data. BMP7 had a strong effect on gene expression. The cellular functions most strongly affected were regulation of transcription and development. The observed transcriptional response followed a temporal sequence. Hierarchical clustering revealed distinct differences in the response of individual cell lines to BMP7, but also highlighted a synexpression group of genes. Finally, this study provides a list of potential novel BMP target genes relevant in breast cancer. Two-condition experiment, vehicle-treated vs. BMP7-treated. Five cell lines were tested at six time points each, what makes a total of 30 samples. RNA samples from three biological replicates were pooled before hybridization.
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