title: Angiogenic activity of breast cancer patients' monocytes reverted by combined use of systems modeling and experimental approaches.
abstract: Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, 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. In addition, 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. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.
authors.affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Guex
authors.affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.
authors.forename: Isaac
authors.initials: I
authors.lastname: Crespo
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Sylvian
authors.initials: S
authors.lastname: Bron
authors.affiliation: Centre du Sein, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Lausanne, Switzerland; Department of Gynecology and Obstetrics, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Lausanne, Switzerland.
authors.forename: Assia
authors.initials: A
authors.lastname: Ifticene-Treboux
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Eveline
authors.initials: E
authors.lastname: Faes-Van't Hull
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Solange
authors.initials: S
authors.lastname: Kharoubi
authors.affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.
authors.forename: Robin
authors.initials: R
authors.lastname: Liechti
authors.affiliation: Department of Oncology, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Lausanne, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Werffeli
authors.affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.affiliation: Hopital Ophtalmique Jules-Gonin, Lausanne, Switzerland.
authors.forename: Francois
authors.initials: F
authors.lastname: Majo
authors.affiliation: Hopital Ophtalmique Jules-Gonin, Lausanne, Switzerland.
authors.forename: Michäel
authors.initials: M
authors.lastname: Nicolas
authors.affiliation: Merck Group, Darmstadt, Germany.
authors.forename: Julien
authors.initials: J
authors.lastname: Laurent
authors.affiliation: Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Garg
authors.affiliation: Centre du Sein, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Lausanne, Switzerland.
authors.forename: Khalil
authors.initials: K
authors.lastname: Zaman
authors.affiliation: Institute of Pathology, University of Lausanne, Switzerland and Institute of Pathology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Stevenson
authors.affiliation: Department of Medicine, University of Fribourg, Fribourg, Switzerland.
authors.forename: Curzio
authors.initials: C
authors.lastname: Rüegg
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.affiliation: Centre du Sein, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Lausanne, Switzerland; Department of Gynecology and Obstetrics, CHUV (Centre Hospitalier Universitaire Vaudois), University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delaloye
authors.affiliation: The Vital-IT, SIB (Swiss Institute of Bioinformatics), University of Lausanne, Lausanne, Switzerland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Doucey
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D002460:Cell Line; D019295:Computational Biology; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008954:Models, Biological; D009000:Monocytes / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016207:Cytokines