Andrea Califano, Columbia University, "Elucidating master integrators of tumor-related phenotypes"

Sep 21 2010, 11:00 am
Distinguished Lecture Series Guest Speaker: 

Andrea Califano

Professor, Biomedical Informatics, Columbia University
Chief, Division of Biomedical Informatics
Director, Columbia Initiative in Systems Biology
Director, Center for the Multiscale Analysis of Genetic Networks
Associate Director for Bioinformatics, Irving Cancer Research Center

Date & Time: 
Tuesday, September 21, 2010, 11:00AM
Klaus 1116E
Jeffrey Skolnick
The identification of genes acting synergistically as master regulators of physiologic and pathologic cellular phenotypes is a key open problem in systems biology, Here we use a molecular interaction based approach to identify the repertoire of transcription factors (TFs) of a master regulatory module responsible for synergistic activation of a tumor-specific signature. Specifically, we used the ARACNe algorithm and other computational tools to infer regulatory interactions responsible for initiating and maintaining the mesenchymal phenotype of Glioblastoma Multiforme (GBM), previously associated with the poorest disease prognosis. Expression of mesenchymal genes is a hallmark of aggressiveness but the upstream regulators of the signature are unknown. Starting from the unbiased analysis of all TFs, we identify a highly interconnected module of six TFs jointly regulating >75% of the genes in the signature. Two TFs (Stat3 and C/EBPb), in particular, display features of initiators and master regulators of module activity. Biochemical validation confirms that the TFs in the module bind to the inferred promoters in vivo and ectopic expression of the master TFs activates expression of the mesenchymal signature. These effects are sufficient to trigger mesenchymal transformation of neural stem cells, which become highly tumorigenic in vivo, and promote migration and invasion. Conversely, silencing of Stat3 and C/EBPb in human glioma cells leads to collapse of the mesenchymal signature and reduction of tumor aggressiveness. Our results reveal that activation of a small transcriptional module is necessary and sufficient to induce a mesenchymal phenotype in malignant brain tumors.
Additional Info: 

Dr. Califano's interests are broadly defined within the field of Systems Biology, with specific application to human malignancies. In particular his lab has spearheaded early efforts to assemble genome-wide, context-specific maps of molecular interactions in human cells, by integrating several reverse engineering approaches. These maps have shown significant promise in the rational elucidation of both physiological and pathological phenotypes. Over the last few years, his lab has assembled biochemically validated, genome-wide map of transcriptional and post-transcriptional interaction in several human cell contexts, including B cell, Breast Carcinoma, Glioma, and normal and tumor-related Stem Cells. These maps are being extensively used for the unbiased dissection of dysregulated pathways in related human malignancies. The Califano lab integrates the development of analytical methodologies with high-throughput experimental assays necessary for data generation and biochemical/biological validation.

Faculty Website
Lab Website
Center for Computational Biology and Bioinformatics (C2B2)
Multiscale Analysis of Genomic and Cellular Networks (MAGNet)
Herbert Irving Comprehensive Cancer Center
Andrea Califano - Seminar Flier.jpg

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