title: Cell-intrinsic adaptation of lipid composition to local crowding drives social behaviour.
abstract: Cells sense the context in which they grow to adapt their phenotype and allow multicellular patterning by mechanisms of autocrine and paracrine signalling. However, patterns also form in cell populations exposed to the same signalling molecules and substratum, which often correlate with specific features of the population context of single cells, such as local cell crowding. Here we reveal a cell-intrinsic molecular mechanism that allows multicellular patterning without requiring specific communication between cells. It acts by sensing the local crowding of a single cell through its ability to spread and activate focal adhesion kinase (FAK, also known as PTK2), resulting in adaptation of genes controlling membrane homeostasis. In cells experiencing low crowding, FAK suppresses transcription of the ABC transporter A1 (ABCA1) by inhibiting FOXO3 and TAL1. Agent-based computational modelling and experimental confirmation identified membrane-based signalling and feedback control as crucial for the emergence of population patterns of ABCA1 expression, which adapts membrane lipid composition to cell crowding and affects multiple signalling activities, including the suppression of ABCA1 expression itself. The simple design of this cell-intrinsic system and its broad impact on the signalling state of mammalian single cells suggests a fundamental role for a tunable membrane lipid composition in collective cell behaviour.
authors.affiliation: Faculty of Sciences, Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Frechin
authors.affiliation: 1] Faculty of Sciences, Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland [2] Life Science Zurich Graduate School, Ph.D. program in Systems Biology. ETH Zurich and University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stoeger
authors.affiliation: Faculty of Sciences, Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Daetwyler
authors.affiliation: Department of Biochemistry, University of Geneva, 1205 Geneva, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gehin
authors.affiliation: 1] Faculty of Sciences, Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland [2] Life Science Zurich Graduate School, Ph.D. program in Systems Biology. ETH Zurich and University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Nico
authors.initials: N
authors.lastname: Battich
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, 8057, Zurich, Switzerland.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Damm
authors.affiliation: Institute of Molecular Systems Biology, ETH Zurich, 8057, Zurich, Switzerland.
authors.forename: Lilli
authors.initials: L
authors.lastname: Stergiou
authors.affiliation: Department of Biochemistry, University of Geneva, 1205 Geneva, Switzerland.
authors.forename: Howard
authors.initials: H
authors.lastname: Riezman
authors.affiliation: Faculty of Sciences, Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Pelkmans
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000222:Adaptation, Physiological; D000818:Animals; D002450:Cell Communication / Q000502:physiology*; D002452:Cell Count; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry*; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D064286:ATP Binding Cassette Transporter 1; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D051416:Focal Adhesion Protein-Tyrosine Kinases