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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.
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