Swiss Institute of Bioinformatics - SWISS-PROT Release: New Possibilities For The Treatment Of Breast Cancer Arise, With The Help Of Mathematics

A means of reprogramming a flawed immune response into an efficient anti-tumoral one was brought to light by the results of a translational and interdisciplinary trial relating to breast cancer(1). Thanks to the innovative combination of mathematical modelisation and experimentation, only 20 tests were necessary, whereas traditional experimentation would have required 596 tests to obtain the same results.

The study was jointly conducted by Doctor Marie-Agnès Doucey (Experimental oncology, Centre Ludwig de l’UNIL pour la recherche sur le cancer), Professor Ioannis Xenarios (UNIL, SIB, Vital-IT) and Professor Jean-François Delaloye (Breast care center-CHUV, UNIL). Beyond demonstrating the continued collaboration between three of Switzerland’s leading scientific institutions, the trial is noteworthy for its combination of experimental oncology and modelisation. Indeed, it is the first such trial to exploit modelisation to identify efficient therapeutic approaches to be used on cells of breast cancer patients. The funding awarded by the Fond National Suisse pour la Recherche Scientifique and the publication of its results in the scientific review PLOS Computational Biology1 further give weight to both the validity and to the potential of its findings.

The dialogue between monocyte and tumor

Monocytes are immune cells present in the blood. They are consequently also found in tumors. In this setting, monocytes are known to promote the development of the tumoral blood vessels (referred to as their angiogenic action) and to suppress the immune response directed at the tumor (referred to as their immunosuppressive action). As crucial as these are to the development of the tumor, the underlying mechanisms which give rise to these actions are as yet relatively unknown in the field of human cancers.

Taking an interdisciplinary view to find the weakness

The novel approach undertaken, made possible by the interdisciplinarity of a CHUV, UNIL and SIB consortium, consists in combining clinical and experimental oncology with modelisation. The result is an ability to identify these mechanisms and to block the angiogenic and immunosuppressive actions of monocytes in breast cancer.

The trial revealed that, in patients suffering from breast cancer, once blood monocytes are present in the tumor, they considerably increase their angiogenic and immunosuppressive activity. This observation indicates that the tumor has the ability to shape monocyte activities to its advantage.

The key objective of the trial was consequently to block the tumoral monocytes’ angiogenic and immunosuppressive capacities. This implied identifying the molecular mechanisms behind this activity. Bearing in mind the scarcity of monocytes within a tumor and the generally small size of tumor samples, the challenge was considerable. It is against such a backdrop that the innovative combination of mathematical modelisation and experimentation demonstrated its strengths.

Blocking the signals

A Boolean model of monocyte behavior was built, based on experimental data. This model was then drawn on to predict which type of treatments would be able to interfere with these monocyte activities. The predictions were tested via experimentation on tumoral monocytes from patients and one double-treatment was earmarked as being extremely efficient. The treatment inhibits the signaling pathways linked to the kinase receptors TIE-2 and VEGFR which act in synergy to control the angiogenic and immunosuppressive actions of tumoral monocytes.

Advantages and discoveries

The advantages of this approach are two-fold: the modelisation is able to frame the experimentation, and new treatments can be discovered through optimum use of resources and patient samples. By way of comparison, traditional experimentation would have required 596 tests to obtain the same results, whereas only 20 tests were necessary with this new approach.

The trial led to a further trail of discovery. The tumoral monocytes are highly adaptable; as a result of the double treatment they transform themselves into cells capable of giving rise to an immune response directed against the tumor. The results underline that tumoral monocytes represent a new treatment target and suggest that this double treatment could contribute to an immunotherapy approach in the treatment of breast cancer.

Publication in PLOS Computational Biology, ploscompbiol.org

(1) Angiogenic activity of breast cancer patients’ monocytes reverted by combined use of systems modeling and experimental approaches

Nicolas Guex1*, Isaac Crespo1*, Sylvian Bron2, Assia Ifticene-Treboux3, Eveline Faes-van’t Hull2, Solange Kharoubi2, Robin Liechti1, Patricia Werffeli4, Mark Ibberson1, Francois Majo5, Michaël Nicolas5, Julien Laurent6, Abhishek Garg7, Khalil Zaman3, Hans-Anton Lehr8, Brian J. Stevenson1, Curzio Rüegg9, George Coukos2, Jean-François Delaloye3, Ioannis Xenarios1 and Marie-Agnès Doucey2

1 Vital-IT, SIB Swiss Institute of Bioinformatics, University of Lausanne, Switzerland

2Ludwig Center for Cancer Research, University of Lausanne, Switzerland

3Centre du Sein, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Switzerland

4Department of oncology, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Switzerland

5Hopital Ophtalmique Jules-Gonin, Lausanne, Switzerland

6Merck Group, Darmstadt, Germany

7Harvard Medical School, Boston, United States

8Institute of Pathology, University of Lausanne, Switzerland and Institute of Pathology, Johannes Gutenberg University, Mainz, Germany

9Department of Medicine, University of Fribourg, Switzerland

10Department of gynecology and obstetrics, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Switzerland

* These authors contributed equally

For further information contact:
Marie-Agnès Doucey
Ludwig @UnilBiopole III
Chemin des Boveresses 155
CH-1066 Epalinges
Fax: + 41 21 692 39 55
Email: Marie-Agnes.Doucey@unil.ch
Ioannis Xenarios
Université de Lausanne
Vital-IT, SIB Swiss Institute of Bioinformatics
Le Génopode
CH-1015 Lausanne
Tel: +41 21 692 40 31
Fax: +41 21 692 40 65
Email: ioannis.xenarios@isb-sib.ch

About SIB

SIB Swiss Institute of Bioinformatics is an academic non-profit foundation recognized of public utility. It federates bioinformatics activities throughout Switzerland. Its mission is to provide world-class core bioinformatics resources including databases, software, internet and high-performance computing servers as well data analysis support to the national and international life science research community.

SIB also provides leading educational services and bioinformatics research. It has a long-standing tradition of producing state-of-the-art software for the life science research community, as well as carefully annotated databases, such as UniProtKB/Swiss-Prot, the world’s most widely used source of information on proteins. SIB includes 56 world-class research and service groups, which bring together more than 650 scientists in the fields of proteomics, transcriptomics, genomics, systems biology, structural bioinformatics, evolutionary bioinformatics, biophysics and population genetics, located in the Swiss cantons of Basel, Bern, Fribourg, Geneva, Ticino, Vaud and Zurich.

SIB’s expertise is widely valued and life scientists all over the world use its services.

www.isb-sib.ch

About Vital-IT and Swiss-Prot

Vital-IT is a bioinformatics competence centre of SIB. It provides computational resources, consultancy and training to connect fundamental and applied research, and to support and collaborate with life scientists in Switzerland and beyond. The multidisciplinary team provides expertise and maintains a high-performance computing and storage infrastructure, so as to help develop, maintain and extend life science and medical research. It has become an essential partner for life science research in Switzerland.

www.vital-it.ch

About bioinformatics

Over the past 30 years, major new biological and medical research techniques, along with significant developments in computing, have increased both the amount and complexity of biological data such as those generated by DNA sequencing. This is why scientists increasingly use information technology to study biological data – a science called bioinformatics.

Life scientists use bioinformatics to store, process and analyse large quantities of data to advance their knowledge and understanding of biological processes. This, in turn, can lead to scientific breakthroughs that enhance our quality of life.

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