Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from colon fibroblasts treated with Sonic hedgehog homolog (SHH)

ABSTRACT: Canonical Hedgehog (Hh) signaling regulates the expression of genes that are critical to the patterning and development of a variety of organ systems. In adult, both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligand, activation occurs within the stromal microenvironment (Yauch et al., 2009). In situ hybridization of the pathway target gene, Ptch1, shows that signaling is located at stromal perivascular fibroblast-like cells in xenograft tumor sections derived from Hh-expressing colorectal cancer cell lines. To study the downstream genes regulated by Hh signaling, we treated a primary human colon myofibroblast, CCD-18Co, with SHH (1 ug/ml) or no treatment (control) in serum-free medium supplemented with 0.1% BSA for 72 hrs and performed microarray analysis (Affymetrix U133P) on these samples. Three biological replicates of SHH stimulated and three replicates of unstimulated primary colon myofibroblast cells CCD-18Co were used in the experiment to analyze their gene expression.

ORGANISM(S): Homo sapiens

SUBMITTER: Weiwei Chen

PROVIDER: E-GEOD-29316 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells.

Chen Weiwei W Tang Tracy T Eastham-Anderson Jeff J Dunlap Debra D Alicke Bruno B Nannini Michelle M Gould Stephen S Yauch Robert R Modrusan Zora Z DuPree Kelly J KJ Darbonne Walter C WC Plowman Greg G de Sauvage Frederic J FJ Callahan Christopher A CA

Proceedings of the National Academy of Sciences of the United States of America 20110519 23

Hedgehog (Hh) signaling is critical to the patterning and development of a variety of organ systems, and both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligands, activation occurs within the stromal microenvironment. Testing whether ligand-driven Hh signaling promotes tumor angiogenesis, we found that Hh antagonism reduced the vascular density of Hh-producing LS180 and SW480 xenografts. ...[more]

PMID: 21597001

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Project description:Stomach and intestinal epithelial cells are maintained by the activity of stem cells located in the isthmus and crypt, respectively1,2. Recent studies have demonstrated a surprisingly conserved role for Wnt signaling in stomach and intestinal development and stem cells3,4. Although accumulating evidence suggests that intestinal stromal cells secrete Wnt ligands to promote stem cell renewal5-10, the source of stomach Wnt ligands is still unclear. Moreover, how these gastrointestinal stem cell niche signals are produced is currently unknown. By performing single cell analysis of gastrointestinal stromal cells, we identified cell populations with transcriptome signatures that are conserved between the stomach and intestine. In close proximity to gastrointestinal epithelial cells, these cells highly expressed pericyte markers and Wnt ligands. They also were enriched for Hh signaling, which plays a key role in gut development11,12. A recent study has shown that intestinal pericryptal cells co-express Hh target and Wnt ligand genes8. To define their relationship, we analyzed mice with Hh gain of function in the pericyte-like stromal cells conserved between the stomach and intestine, and found increased levels of Wnt ligands, supporting Hh regulation of stromal Wnt ligand expression. Moreover, utilizing Sufu and Spop double knockout mice, which stabilized GLI2, a key Hh mediator in the gut, we were able to map GLI2 binding sites genome-wide and analyze super enhancers. This work demonstrates GLI2 activation of stromal Wnt ligands through enhancers that are conserved between the stomach and intestine. To determine the significance of Wnt secreting gastrointestinal stromal cells, we genetically inhibited Wnt secretion from the perictye-like or broad stromal cells, demonstrating their roles in gastrointestinal regeneration and development, respectively. Our work not only identifies the conserved gastrointestinal stromal niche cell populations but also reveals their underlying signaling and epigenetic mechanisms.

Project description:Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor of many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling profoundly depend on interactions with other pathways such as epidermal growth factor receptor-mediated signaling which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. We demonstrate that the human medulloblastoma cell line Daoy possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic Hedgehog or Smoothened agonist induced expression of GLI1 protein and prevented processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed on the transcriptomic as well as proteomic level. Daoy cells responded to the co-treatment by downregulating GLI1, PTCH, and HHIP on the transcript level which was also seen when Amphiregulin (AREG) was used instead of EGF. The finding that EGFR signaling silences proteins acting as negative regulators of HH signaling is firstly described here as a novel crosstalk mechanism. Furthermore, combined EGFR/HH signaling maintains high GLI1 protein levels contrasting its downregulation on the transcript level. On the other hand, high level synergism was observed with respect to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile pointing to more wide-spread, yet context-dependent, interactions between HH/GLI and growth factor receptor signaling in human malignancies. To study interactions between HH- and EGF-induced signaling, time-resolved measurements were carried out over a period of 24 h at 14 different time points after stimulation by EGF with and without additional stimulation by SHH. Furthermore, as a control, cells without any stimulation by EGF and SHH (control) and cells in the presents of SHH were analyzed. Overall, three biological replicates of 60 different treatment/timepoints were analyzed yielding 180 different samples.

Dataset Information

Expression data from colon fibroblasts treated with Sonic hedgehog homolog (SHH)

Publications

Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells.

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