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Team Publications Bioinformatics and Computational Systems Biology of Cancer Year of publication 2013 David Cohen, Inna Kuperstein, Emmanuel Barillot, Andrei Zinovyev, Laurence Calzone (2013 May 30) From a biological hypothesis to the construction of a mathematical model. Methods in molecular biology (Clifton, N.J.) : 107-25 : DOI : 10.1007/978-1-62703-450-0_6 Summary Mathematical models serve to explain complex biological phenomena and provide predictions that can be tested experimentally. They can provide plausible scenarios of a complex biological behavior when intuition is not sufficient anymore. The process from a biological hypothesis to a mathematical model might be challenging for biologists that are not familiar with mathematical modeling. In this chapter we discuss a possible workflow that describes the steps to be taken starting from a biological hypothesis on a biochemical cellular mechanism to the construction of a mathematical model using the appropriate formalism. An important part of this workflow is formalization of biological knowledge, which can be facilitated by existing tools and standards developed by the systems biology community. This chapter aims at introducing modeling to experts in molecular biology that would like to convert their hypotheses into mathematical models. Virginie Maire, Céline Baldeyron, Marion Richardson, Bruno Tesson, Anne Vincent-Salomon, Eléonore Gravier, Bérengère Marty-Prouvost, Leanne De Koning, Guillem Rigaill, Aurélie Dumont, David Gentien, Emmanuel Barillot, Sergio Roman-Roman, Stéphane Depil, Francisco Cruzalegui, Alain Pierré, Gordon C Tucker, Thierry Dubois (2013 May 24) TTK/hMPS1 is an attractive therapeutic target for triple-negative breast cancer. PloS one : e63712 : DOI : 10.1371/journal.pone.0063712 Summary Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Team Publications Bioinformatics and Computational Systems Biology of Cancer increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer. Paola Vera-Licona, Eric Bonnet, Emmanuel Barillot, Andrei Zinovyev (2013 Apr 30) OCSANA: optimal combinations of interventions from network analysis. Bioinformatics (Oxford, England) : 1571-3 : DOI : 10.1093/bioinformatics/btt195 Summary Targeted therapies interfering with specifically one protein activity are promising strategies in the treatment of diseases like cancer. However, accumulated empirical experience has shown that targeting multiple proteins in signaling networks involved in the disease is often necessary. Thus, one important problem in biomedical research is the design and prioritization of optimal combinations of interventions to repress a pathological behavior, while minimizing side-effects. OCSANA (optimal combinations of interventions from network analysis) is a new software designed to identify and prioritize optimal and minimal combinations of interventions to disrupt the paths between source nodes and target nodes. When specified by the user, OCSANA seeks to additionally minimize the side effects that a combination of interventions can cause on specified off-target nodes. With the crucial ability to cope with very large networks, OCSANA includes an exact solution and a novel selective enumeration approach for the combinatorial interventions’ problem. Year of publication 2012 Virginie Maire, Fariba Némati, Marion Richardson, Anne Vincent-Salomon, Bruno Tesson, Guillem Rigaill, Eléonore Gravier, Bérengère Marty-Prouvost, Leanne De Koning, Guillaume Lang, David Gentien, Aurélie Dumont, Emmanuel Barillot, Elisabetta Marangoni, Didier Decaudin, Sergio Roman-Roman, Alain Pierré, Francisco Cruzalegui, Stéphane Depil, Gordon C Tucker, Thierry Dubois (2012 Nov 13) Polo-like kinase 1: a potential therapeutic option in combination with conventional chemotherapy for the management of patients with triplenegative breast cancer. Cancer research : 813-23 : DOI : 10.1158/0008-5472.CAN-12-2633 Summary Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2 Team Publications Bioinformatics and Computational Systems Biology of Cancer carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G(2)-M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3