Fondation MEDIC

www.fondation-medic.ch

Reprogramming Tie-2 expressing monocytes in breast cancer to promote protective anti-tumor immune responses
[19.10.2016]
Project leader – Marie-Agnès Doucey
Marie-Agnès Doucey

Marie-Agnès Doucey is engineer in biotechnology from the ESBS (Ecole Supérieure de Biotechnologie de Strasbourg, France) since 1994. She completed her studies at the Friedrich-Miescher Institute of Basel with a Ph.D in biochemistry in 1998. From 1999 to 2003, she pursued post-doctoral training in immunology at the Ludwig Institute for Cancer Research and at the Institute of Biochemistry of Epalinges. In 2004 she became a project leader at the CHUV. From 2009 to 2013, she was a project leader at the Division of Experimental Oncology of Lausanne. In 2013, she joined the group of Pr. George Coukos at the Ludwig Center for Cancer Research of the the University of Lausanne.

Ludwig Institute for Cancer Research
Biopole III
Chemin des Boveresses 155
CH1066 Epalinges

Tel + 41 21 692 59 60

E-Mail:
Marie-Agnes.Doucey@unil.ch

Group members
 

Sylvian Bron

technician (part time)

Angélique Pabois

post-doctoral fellow

Vérène Pignat

technician (part time)

Project description
 

Infiltration of monocytes or macrophages is a common feature of inflammation and tumor angiogenesis, which is receiving increasing attention in an attempt to develop novel therapeutic strategies. The ability of tumoricidal macrophages to recognize and selectively destroy neoplastic cells has been demonstrated in a wide range of experimental systems while tumor-associated macrophages were also reported to promote tumor development, progression and metastasis. The functional heterogeneity of tumor macrophages reflects their plasticity and ability to readily adapt to cues from the microenvironment in which they reside. Thus, while much effort has focused on strategies to block the recruitment of circulating monocytes to tumor tissue, or in the depletion of tumor macrophages in vivo in tumor-bearing mice, newly emerging approaches designed to ‘reprogram’ macrophages with anti-tumor properties are demonstrating promise for cancer immunotherapy. We address the reprograming of pro-tumoral monocytes in human breast cancer using approaches interfacing experimental oncology with computational modeling and nanotechnologies.

  • Interfacing computational and experimental approaches to simulate and predict the behavior of angiogenic monocytes in breast cancer patients.

M.-A. Doucey, in collaboration with Xenarios (SIB and Vital-IT) and J.-F. Delaloye (CHUV)

We demonstrated that the vast majority (> 95%) of monocytes infiltrating breast carcinoma co-express TIE-2/Tek and VEGFR and that the expression of these receptor tyrosine kinases control their pro-angiogenic and immune suppressive functions. In addition, these monocytes are lymphangiogenic and incorporate into tumor lymphatic vessels but not into lymphatics of adjacent non-neoplastic tissues. Importantly, all these pro-tumoral functions are critically shaped by the tumor microenvironment and driven by TIE-2 and VEGFR kinase activities.

We developed a novel strategy combining Boolean modeling and experimental approaches to simulate and predict the behavior of angiogenic monocytes in breast cancer. The immediate outcome of our in-silico simulation for oncology was to focus on the most clinically relevant monocytic ligands and to unravel treatments abrogating TEM proangiogenic activity at breast tumor sites. We predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. Inferred TEM regulatory network (panel C) accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic and pro-tumoral activities. Gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. These results indicate that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.

  • Nano-Bio-Sensors for the detection of soluble angiogenic proteins in breast tumors.

M.-A. Doucey in collaboration with S. Carrara (EPFL)

We show that the breast tumor microenvironment shapes the phenotype and the function of pro-tumoral monocytes. However, to date, the approaches to profile inflammatory and angiogenic factors in specific tumor zones are extremely limited. In collaboration with Dr. Sandro Carra from the EPFL, we produced a silicon nanowire-based sensor to characterize the tumor microenvironment (panel B). The silicon nanowire is a semi-conductor functionalized with specific antibodies and antigen detection is based on a memory resistor effect. This nanowire-based sensor display an outstanding sensitivity and can detect VEGF-A in a tumor extract in the fentomolar range. This sensor represents a novel approach to characterizing the tumor microenvironment at a scale that has never been achieved before in biological specimens.

Publications
 
2015 / DOI:10.1109/JSEN.2015.2456336
Ioulia Tzouvadaki · Francesca Puppo · Marie-Agnes Doucey · Giovanni De Micheli · Sandro Carrara. Computational Study on the Electrical Behavior of Silicon Nanowire Memristive Biosensors. IEEE Sensors Journal
» PubMed
2015 / 10.1080/2162402X.2015.1073882
Bron S, Henry L, Faes-van’t Hull E, Turrini R, Vanhecke D, Guex N, Ifticene-Treboux A, Majo F, Nicolas M, Iancu EM, Semilietof M, Rufer N, Lehr HA, Xenarios I, Coukos G, Delaloye J.-F., Doucey M-A. TIE-2-expressing monocytes are lymphangiogenic and incorporate specifically into lymphatics of human breast cancer. Oncoimmunology
» PubMed
2015 / e1046674.
Doucey MA, Xenarios I. Oncoimmunology. 2015 Jul 7;4(11):e1046674. eCollection 2015 Nov. Toward a rational design of combination therapy in cancer. Oncoimmunology
» PubMed
2015 / Conference Paper
Tzouvadaki I, Puppo F, Doucey M-A, De Micheli G, Carrara S. Modeling Memristive Biosensors. Proceedings of the IEEE Sensors, Busan, South Korea.
» PubMed
2015 / DOI:10.1109/JSEN.2015.2433836
Francesca Puppo · Marie-Agnes Doucey · Jean-Francois Delaloye · Thomas S.Y. Moh · Gregory Pandraud · Pasqualina M. Sarro · Giovanni De Micheli · Sandro Carrara. SiNW-FET in-Air Biosensors for High Sensitive and Specific Detection in Breast Tumor Extract. IEEE Sensors Journal
» PubMed
2015 / Conference paper
Lotfi A, Puppo F, Doucey M-A, De Micheli G and Carrara S. Reliable Redundancy with Memristive-Biosensors to achieve Statistical Significance in Immunosensing. IWASI 2015, 6th IEEE International Workshop on Advances in Sensors and Interfaces, Gallipoli (Le), Italy
» PubMed
2014
Puppo F, Doucey M-A, Delaloye JF, Moh T, Pandraud G, Sarro PM, De Micheli G and Carrara S. High Sensitive Detection in Tumor Extracts with SiNW-FET in Air-Biosensors. Proceeedings of the IEEE Sensors, Valencia, Spain, Nov 3-5
» PubMed
2014
Puppo F, Doucey M-A, Di Ventra M, De Micheli G and Carrara S., Proceedings of the IEEE International Symposium on Circuits and Systems (ISCAS, 2014, Melbourne, Australia, June 1-5, 2014.. Memristor-Based Devices for Sensing. Proceedings of the IEEE International Symposium on Circuits and Systems, ISCAS, 2014, Melbourne, Australia
» PubMed
2014 / 10.1371
N. Guex, I. Crespo, S. Bron, A. Ifticene-Treboux, E. Faes van’t Hul, S. Kharoubi, R. Liechti1, P. Werffeli, M. Ibberson, F. Majo, M. Nicolas, J. Laurent, A. Garg, K. Zaman, H-A. Lehr, B. J. Stevenson1, C. Rüegg, G. Coukos, J.-F. Delaloye, I. Xenarios and M.-A. Doucey. Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches. PLOS Computational Biology
» PubMed
2014 / Conference Paper
Francesca Puppo · Marie-Agnes Doucey · Massimiliano Di Ventra · Giovanni De Micheli · Sandro Carrara. Memristor-based devices for sensing. IEEE International Symposium on Circuits and Systems (ISCAS) Melbourne, Australia
» PubMed
2014 / e29080
Van't Hull EF, Bron S, Henry L, Ifticene-Treboux A, Turrini R, Coukos G, Delaloye JF, Doucey MA.. Bone marrow-derived cells are implicated as a source of lymphatic endothelial progenitors in human breast cancer. Oncoimmunology
» PubMed
2014 / e29080
Eveline Faes van’t Hull, Sylvian Bron, Luc Henry, Assia Ifticene-Treboux, Riccardo Turrini, George Coukos, Jean-François Delaloye, Marie-Agnès Doucey. Bone marrow-derived cells are implicated as a source of lymphatic endothelial progenitors in human breast cancer. Oncoimmunology
» PubMed
2013 / 10.1158/1078-0432.CCR-12-3181
Ibberson M, Bron S, Guex N, Faes-Van't Hull E, Ifticene-Treboux A, Henry L, Lehr HA, Delaloye JF, Coukos G, Xenarios I, Doucey MA. TIE-2 and VEGFR Kinase Activities Drive Immunosuppressive Function of TIE-2-Expressing Monocytes in Human Breast Tumors. Clin Cancer Res
» PubMed
2013 / Conference Paper
Puppo F, Doucey M.-A., Moh T, Pandraud G, Sarro L, De Micheli G, Carrara S. Femto-Molar Sensitive Field Effect Transistor Biosensors Based on Silicon Nanowires and Antibodies. IEEE Sensors Conference, 03 Nov - 06 Nov 2013, Baltimore
» PubMed
2013 / Conference Paper
Puppo, Francesca; Doucey, Marie-Agnès; Moh, Thomas S. Y.; Pandraud, Grégory; Sarro, Pasqualina M.; De Micheli, Giovanni; Carrara, Sandro. Femto-Molar Sensitive Field Effect Transistor Biosensors Based on Silicon Nanowires and Antibodies. Proceedings of the IEEE Sensors 2013, IEEE Sensors, Baltimore, Maryland, USA, November 4-6, 2013
» PubMed
2013 / doi:10.1109/TNB.2013.2295517
Puppo F, Dave A, Doucey M.-A., Sacchetto D, Leblebici Y, De Micheli G, Baj-Rossi C, Carrara S. Memristive Biosensors under Varying Humidity Conditions. IEEE Transactions on Nanobioscience
» PubMed
2012 / 10.1371
Brunner JM, Plattet P, Doucey MA, Rosso L, Curie T, Montagner A, Wittek R, Vandelvelde M, Zurbriggen A, Hirling H, Desvergne B.. Morbillivirus glycoprotein expression induces ER stress, alters Ca2+ homeostasis and results in the release of vasostatin. PLoS One
» PubMed
2012 / 10.1016/j.snb.2012.04.089
Carrara S, Sacchetto D, Doucey M.-A., Bay-Rossi C, De Micheli G, Leblebici Y. Memristive-Biosensors: A new detection method by using Nanofabricated Memristors. Sensors and Actuators B: Chemicals
» PubMed
2011 / 10.1007/s12668-011-0002-9
Sacchetto D, Doucey M.-A., De Micheli G, Leblebici Y, Carrara S. New Insight on Biosensing by Nanofabricated Memristors. New Insight on Biosensing by Nanofabricated Memristors
» PubMed
2011 / 10.1158/0008-5472.CAN-10-3684
Laurent J, Hull EF, Touvrey C, Kuonen F, Lan Q, Lorusso G, Doucey MA, Ciarloni L, Imaizumi N, Alghisi GC, Fagiani E, Zaman K, Stupp R, Shibuya M, Delaloye JF, Christofori G, Rüegg C. Proangiogenic factor PlGF programs CD11b(+) myelomonocytes in breast cancer during differentiation of their hematopoietic progenitors. Cancer Res. 2011 Jun 1;71(11):3781-91
» PubMed
2009 / 10.1002/pmic.200800359
Brembilla NC, Cohen-Salmon I, Weber J, Rüegg C, Quadroni M, Harshman K, Doucey MA. Profiling of T-cell receptor signaling complex assembly in human CD4 T-lymphocytes using RP protein arrays. Proteomics. 2009 Jan;9(2):299-309
» PubMed
2008 / 10.1182/blood-2008-01-134486
Brembilla NC, Weber J, Rimoldi D, Pradervand S, Schütz F, Pantaleo G, Rüegg C, Quadroni M, Harshman K, Doucey MA. c-Cbl expression levels regulate the functional responses of human central and effector memory CD4 T cells. Blood. 2008 Aug 1;112(3):652-60
» PubMed