Systems Biology Journal Club

Image courtesy of VTT Biotechnology

THIS YEAR'S GOAL: We will provide an introduction to molecular/biolgical pathways and the role they play in cancer biology and, more generally, systems biology research. Molecular pathways provide a foundation upon which high-throughput data can be integrated thus allowing for a system-theoretic framework within which one can study the dynamic interactions of a cell. The bioinformatics community is actively developing a broad array of pathway databases. Many OSU researchers are availing themselves to these pathway databases and employing this new research tool to advance our understanding of cancer development and treatment.

AFFILIATIONS: This journal club is an integral function of the core C component of the Center for Integrative Cancer Biology. For further information about this quarter's journal club or to be added to the mailing list, please contact Dustin Potter or Baltazar Aguda.

Our counterpart, the Epigenetic Journal Club, meets Thursdays at 8:00 AM in Tzagournis, room 634. Contact Laura Smith for more information.

Title: Monotone systems: stability and oscillations.

Abstract: Monotone systems are dynamical systems with strong stability properties, and they are strongly associated with positive feedback interactions. The recent work by E. Sontag and collaborators suggests that the theory of monotone dynamical systems can be used to model the behavior of various gene regulatory networks in molecular biology.

In this talk, I will provide an overview of some of the main results of this theory, which fall into two categories. The first result, known as a 'small gain theorem', guarantees the global asymptotic stability of various dynamical systems under negative feedback, even with the addition of time delays. A second type of result describes the emergence of oscillatory behavior in different biological contexts.

Title: Microvesicles and their involvement in mediating macrophage differentiation.

Abstract: Microvesicles facilitate communication between cells. Many cells including macrophages, platelets, and tumors release small microvesicles containing nucleic acids and/or proteins with or without activation. Several investigators reported that processed mRNA is contained within these vesicles. These mRNAs encode transcription factors which are known to regulate angiogenesis, cell growth, and differentiation.

Macrophages critically regulate bacterial infections through phagocytosis of foreign antigens. In addition to their innate immune function, macrophages contribute to tissue remodeling and wound healing. Macrophages are derived from peripheral blood monocytes. Interestingly, many macrophages differ in appearance and function based on their microenvironment, including tissue macrophages, dendritic cells, tumor-associated macrophages (TAMs), microgilia, Kupffer cells, and osteoclasts. TAMs are a component of the inflammatory response to solid tumors.

Abnormalities in monocytes/macrophages maturation and/or function contribute to a wide variety of malignancies and human disease including inflammatory diseases and cardiovascular disease. Our laboratory found that macrophages are critical for solid tumor metastases by regulating angiogenesis. Our data also suggested that mature macrophages are important for chronic inflammation in pulmonary fibrosis. For these reasons, we are interested in exploring novel mechanisms which regulate monocyte differentiation to macrophages.

We have preliminary data that microvesicles released during macrophage differentiation induce monocytes to survive and differentiate. Our studies have identified a RNA component within the vesicles. Understanding the role of microvesicles in regulating macrophages may provide insight in inflammatory diseases.

Title: Signaling across cell boundaries: genetic analysis of the ras/ets2 pathway in the breast tumor microenvironment

Abstract: Cancer results from a multi-step series of genetic changes in genes that control cell growth, differentiation and apoptosis. In addition to this genetic complexity, it is increasingly appreciated that the cellular complexity of the tumor microenvironment contributes directly to cancer initiation, progression and metastasis. We are interested in understanding interactions between signaling pathways locating in the different cell types involved in the complex biological process of cancer cell progression and metastasis.

For example, a breast tumor is composed not only of the epithelial-cell derived tumor cell, but also stromal cells, endothelial cells, and immune cells including macrophages, B-cells and T-cells. It is the interaction of these cell types through complex signaling networks that are likely to be important for tumor cell progression and metastasis, and not just the action of individual signaling pathways within the epithelial tumor cell. Understanding and targeting such intercellular networks of communication holds great promise for new advances in the diagnosis and treatment of cancer.

Using mouse genetic techniques, we have begun removing genes of interest within specific cell compartments in breast tumor models, such as tumor fibroblasts and tumor macrophages. We have found these mutations in microenvironment cell types affect tumor growth and metastasis. We are using molecular and functional genomic approaches to begin understanding how affected a gene in one cell type results in changes in other cell types in the tumor microenvironment, including the tumor cells themselves. A long term goal is to develop models that will help us to predict how these interactions occur and to identify the best molecular targets within the microenvironment in human cancers.

Title: The isolation of a Fhit protein complex suggests a novel pathway of apoptosis of cancer cells

Abstract: The fragile histidine triad (FHIT) gene, spanning FRA3B at 3p14.2, the most active human common fragile site, shows abnormal transcripts, promoter hypermethylation and biallelic lost in a large number of different human tumors. Furthermore, its restoration in several malignant cell lines triggers apoptosis in vitro and in preclinical models. However, although FHIT has extensively been demonstrated to be involved in cancer by hundreds of reports, its function as a tumor suppressor remains still obscure, since many attempts of identifying its partners remained inconclusive. Here we describe a proteomics-based approach aimed to identify a Fhit protein complex responsible for triggering apoptosis in Fhit virally-transduced lung cancer cells. Our findings demonstrate that Fhit localizes in both cytosol (where it interacts with Hsp60 and Hsp10) and mitochondria (where, other than Hsp60 and Hsp10, it interacts with proteins responsible for the electron transfer). Interestingly, Fhit restoration significantly increases the production of reactive oxygen species (ROS).
Taken together, these data suggest a novel pathway of Fhit-mediated programmed cell death in malignant cells and open a field of investigation for the search of new anticancer therapeutic approaches.

1. Keng Wee and Baltazar Aguda, "Akt versus p53 in a Network of Oncogenes and Tumor Suppressor Genes Regulating Cell Survival and Death " (August 2006). DOC1
2. B. D. Aguda and Y. Tang, "The kinetic origins of the restriction site in the mammalian cell cycle" (1999) DOC2
3. Baltazar D. Aguda and Christopher K. Algar, "A Structural Analysis of the Qualitative Networks Regulating the Cell Cycle and Apoptosis " (December 2003) DOC3

Title: Analysis of networks of oncogenes and tumor-suppressor genes involved in cell cycle checkpoints, apoptosis, and cell survival

Abstract: Oncogenes and tumor-suppressor genes promote and inhibit, respectively, the progression of carcinogenesis. Networks of interactions among these genes in the G1 cell cycle checkpoint (called the Restriction Point), in the regulation of cell death (apoptosis), and in survival signaling pathways will be illustrated. Modularization and qualitative stability analysis of these networks allowed us to reduce their complexity and to identify key control motifs. In the G1 checkpoint, the positive feedback loops in the interactions among Cdc25A, p27Kip1, and CDK2 generate an instability that can explain the switching behavior associated with the Restriction Point. Recent work on the cross-talk between p53 and Akt, which led to a proposed cell survival-death switch, will also be presented.

1. Baltazar Aguda and Andrew B. Goryachev, "From pathways databases to network models" (September 2006). MBI Technical Report No. 56 (DOC)

Title: Using Pathways Databases to Extract Biological Network Models

Abstract: A brief overview of existing online biological pathways databases will be given. The use of these databases in formulating a network model of the G1 checkpoint in the mammalian cell cycle is then illustrated in detail. Despite the qualitative nature of the information extracted from databases, it will be shown that network structure may already tell us about the stability or instability of the system.

Image courtesy of VTT Biotechnology