Modeling the cell cycle regulation by the RB/E2F pathway Laurence Calzone Service de Bioinformatique U900 Inserm / Ecoles de Mines / Institut Curie Collaborative work with two groups led by: Franois Radvanyi (UMR 144) Emmanuel Barillot (U900/ Ec. Des Mines/ Institut Curie) JSM 2008 Laurence Calzone The role of bioinformatics and systems biology The main purpose is to understand the behavior of a complex system as a whole, as opposed to the behavior of its individual components. More specifically, the goal is: -provide a consensus picture of the cell functioning -integrate information from many experiments and publications -help confirm or infirm hypotheses: check that the mechanism is correct -propose experiments to experimentalists Ideally, the systems biology approach is iterative: 1.Build the molecular map and the corresponding mathematical model from experimental data; 2.Test experimentally theories, phenotypes or hypotheses predicted by the model; 3.Modify/Refine the model according to the biological results; 4.etc. JSM 2008 Laurence Calzone DNA mRNA polypeptide A B C E F D network physiology substrate protein activity product(s) JSM 2008 Laurence Calzone Motivation to work on cancer Cellular processes are based on complex networks of interacting genes and proteins Cancer is a pathology of the processes that govern differentiation, proliferation, apoptosis, that is a disregulation of these networks. The general questions we would like to answer are: How can we describe pathways and model them? What are the pathways involved in a pathology? How to use the pathways to improve predictions? What are the effects of a perturbation on a pathway? etc. The more specific questions we are interested in are: Why are some genes amplified in tumor cells; why and how can genomic alterations lead to cancers; etc. What are the pathways or actors involved in the activation of a protein? Which phenotypes can be predicted from certain perturbations? JSM 2008 Laurence Calzone RB in tumor progression RB (Retinoblastoma) is a cell proliferation regulator: RB is a tumor suppressor that controls cell cycle progression (G0/G1 and G1/S transitions). The importance of the RB pathway is known in cancer: RB is targeted and inactivated by viral oncoproteins (E7) RB pathway is inactivated in most tumoral cells in different ways: - RB gene mutation - Deregulation of the kinases that control its activity Mitogenic Signal CDK4/6 RB RB-P E7 E2F Progression of Cell Cycle CKI (p16) Cyc D JSM 2008 Laurence Calzone Step 1: Build a consensus protein-protein interaction map of RB/E2F network 78 proteins, 169 genes, 208 species, 166 reactions, more than 350 publications JSM 2008 Laurence Calzone Step 2: Make the map usable 1. From the complete network, build a modular view G0 Early G1Late G1SG2M JSM 2008 Laurence Calzone Module RB (no information lost) JSM 2008 Laurence Calzone Step 2: Make the map usable 2. Apply the map to real transcriptome and CGH data: example of bladder cancer (55 bladder tumor + 5 normal samples) - Definition of modules activity in invasive and non-invasive cancers: Invasive cancers: proliferation modules are active and inhibitors of proliferation are inactive Other analysis of the data: Classification of these samples according to their activity reveals the type of alterations that make tumors more invasive than others. upregulated downregulated normal sample level Invasive cancers JSM 2008 Laurence Calzone Perspectives - Apply this method to other cancers (Ewing, retinoblastoma, etc.) - Model the pathway (discrete and numerical) in order to answer specific questions - Other project on modeling apoptosis (in collaboration with experimentalists) JSM 2008 Laurence Calzone Webpage : Interactive map JSM 2008 Laurence CalzoneLoredana Martignetti SITCON project miRNA and sequence analysis JSM 2008 Laurence Calzone