This example shows how SEEK can help users to achieve these three objectives:
- Explore Hedgehog signaling pathway (Hh) across the diverse compendium datasets
- Find out the disease states and cancer types in which Hh pathway genes are co-expressed (i.e. find datasets associated with the Hh pathway)
- Find out other gene candidates in this pathway
Hedgehog (Hh) pathway is a major development and cancer pathway. This pathway is perturbed in cancer patients likely caused by mutations. The pathway is SHH, DHH, IHH ligand dependent and upon ligand binding it produces the transcription factors GLI1, GLI2 which then activate a wide range of downstream processes.
To start exploring this pathway, we enter GLI1 GLI2 PTCH1 as query, which are transcription factors and receptor protein that are markers of this pathway, and central to the machinery.
Figure 1 shows the result of this query. In this figure, panel 1 shows the prioritization of datasets based on the co-expression of the query genes (the top 4 datasets are shown in the figure). These prioritized datasets represent cancer studies where the expression/coexpression of the pathway genes indicate the importance of the Hh pathway activations.
Mouse-over the dataset header to learn about the type of tissues or diseases studied ().
Figure 1: Hh query GLI1 GLI2 PTCH1.
For example, when we examine the top datasets, we have simultaneously discovered Hh activations across a diverse set of disease states, such as medulloblastoma, rhabdoid tumors, lung small-cell carcinoma. Many of these have confirmed literature associations to aberrant Hh signaling    .
Previously, we know that Hh misregulations often result in the constitutive activation of the pathway. Here we use the coexpression of the pathway genes GLI1/2 and PTCH1 as a proxy to represent pathway activity. Coregulations of Hh genes in this case measures active pathway signaling. Retrieved datasets will show pathway expression profiles consistent with activating Hh dysfunction.
Pinpointing disease/cancer types associated with a pathway can be very useful. It can suggest a pathway-based stratification of cancer patients based on pathway profiles, which may lead to useful strategies for treating the patient by targeting the Hh pathway. By looking across thousands of datasets in SEEK, the co-expression landscape across diverse tissue/disease states can now be comprehensively examined.
To answer the third question, panel 2 displays an integrated list of co-expressed genes around the query. These represent genes that are predicted to be associated with Hh. SEEK retrieved many currently known members of Hh machinery, such as SMO, HHIP, BOC, PTCH2. One of the top ranked members that SEEK identified, KIF7 (rank 22/17680) is the homolog of Cos2 protein in Drosophila melanogaster, and is a recently experimentally verified Hh regulator  .