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Example of the project:

Network Analysis of Co-Expressed Metabolic Genes

Metabolic pathways in melanoma and the role of PGC1-alpha in their regulation was carried out by the Bioinformatics Core in support of a study conducted by Drs. Smith and Osterman. A curated list of glutamine utilization genes was used for clustering on 3  different melanoma datasets. A subset of the Gln utilization and associated metabolic genes co-clustered in 2 out of 3 datasets and represent about 30% of melanoma samples. Causal upstream network construction and analysis of the co-clustered metabolic genes implicated PGC1-α among others as a key regulator. Validation of additional microarray data from the Genomics core pointed to the same regulatory hubs. Subsequently, cell growth experiments on melanoma cell lines with different PGC1-α levels showed significant correlation between PGC1-α expression level and doubling time suggesting that PGC1-α  might serve as a surrogate biomarker of disease progression. These data provided preliminary results for a new R0 submitted to NCI. 



Network Analysis of Co-Expressed Metabolic Genes

Tumor-suppressive mechanisms of transcription factor XX

The study of tumor-suppressive mechanisms of transcription factor XX in pancreatic ductal adenocarcinoma show that XX induces the WNT signaling pathway and revealed a subset of 36 WNT activation targets that were down-regulated by XX. The Bioinformatics core helped Dr. Itkin-Ansari with mechanistic biological network reconstruction to uncover pathways from tamoxifen-induced XX to 30 of those targets (A). These are significantly enriched with pancreatic cancer genes and metastases-related genes, showing the role of XX as a potential tumor suppressor. Knowledge-driven pathway reconstruction helped elucidate the mechanisms employed by XX, similar to p53, p16, and SMAD4, or opposite of the oncogenic mechanism of K-RAS (B). Many XX pathways lead through p21, and subsequent inhibition of E2F1 and c-Myc, which leads to down-regulation of multiple cell cycle genes shown by microarray data (overlaid). Collectively, these results underline a tumor suppressive and potentially therapeutic role of XX induction.
Tumor-suppressive mechanisms of transcription factor XX
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