title: Combinatorial code governing cellular responses to complex stimuli.
abstract: Cells adapt to their environment through the integration of complex signals. Multiple signals can induce synergistic or antagonistic interactions, currently considered as homogenous behaviours. Here, we use a systematic theoretical approach to enumerate the possible interaction profiles for outputs measured in the conditions 0 (control), signals X, Y, X+Y. Combinatorial analysis reveals 82 possible interaction profiles, which we biologically and mathematically grouped into five positive and five negative interaction modes. To experimentally validate their use in living cells, we apply an original computational workflow to transcriptomics data of innate immune cells integrating physiopathological signal combinations. Up to 9 of the 10 defined modes coexisted in context-dependent proportions. Each interaction mode was preferentially used in specific biological pathways, suggesting a functional role in the adaptation to multiple signals. Our work defines an exhaustive map of interaction modes for cells integrating pairs of physiopathological and pharmacological stimuli.
authors.affiliation: Department of Immunology, Institut Curie, Paris F-75248, France.|INSERM U932, Paris F-75248, France.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cappuccio
authors.affiliation: Department of Immunology, Institut Curie, Paris F-75248, France.|INSERM U932, Paris F-75248, France.|Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Zollinger
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California, Los Angeles, California 90095, USA.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schenk
authors.affiliation: Laboratoire de Physique Théorique, CNRS, Université P. et M. Curie, École Normale Supérieure, Paris F-75248, France.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Walczak
authors.affiliation: Institut Curie, Bioinformatique et Biologie des Systèmes, Paris F-75248, France.|INSERM U900, Paris F-75248, France.|Mines ParisTech, Fontainebleau, Paris F-77300, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Servant
authors.affiliation: Institut Curie, Bioinformatique et Biologie des Systèmes, Paris F-75248, France.|INSERM U900, Paris F-75248, France.|Mines ParisTech, Fontainebleau, Paris F-77300, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.affiliation: Institut Curie, Bioinformatique et Biologie des Systèmes, Paris F-75248, France.|INSERM U900, Paris F-75248, France.|Mines ParisTech, Fontainebleau, Paris F-77300, France.|CNRS UMR144, Paris F-75248, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hupé
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California, Los Angeles, California 90095, USA.|Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, California 90095, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
authors.affiliation: Department of Immunology, Institut Curie, Paris F-75248, France.|INSERM U932, Paris F-75248, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Soumelis
mesh_terms: D000465:Algorithms; D002478:Cells, Cultured; D003198:Computer Simulation; D003713:Dendritic Cells / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009000:Monocytes / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D049490:Systems Biology