title: Intercellular signaling through secreted proteins induces free-energy gradient-directed cell movement.
abstract: Controlling cell migration is important in tissue engineering and medicine. Cell motility depends on factors such as nutrient concentration gradients and soluble factor signaling. In particular, cell-cell signaling can depend on cell-cell separation distance and can influence cellular arrangements in bulk cultures. Here, we seek a physical-based approach, which identifies a potential governed by cell-cell signaling that induces a directed cell-cell motion. A single-cell barcode chip (SCBC) was used to experimentally interrogate secreted proteins in hundreds of isolated glioblastoma brain cancer cell pairs and to monitor their relative motions over time. We used these trajectories to identify a range of cell-cell separation distances where the signaling was most stable. We then used a thermodynamics-motivated analysis of secreted protein levels to characterize free-energy changes for different cell-cell distances. We show that glioblastoma cell-cell movement can be described as Brownian motion biased by cell-cell potential. To demonstrate that the free-energy potential as determined by the signaling is the driver of motion, we inhibited two proteins most involved in maintaining the free-energy gradient. Following inhibition, cell pairs showed an essentially random Brownian motion, similar to the case for untreated, isolated single cells.
authors.affiliation: NanoSystems Biology Cancer Center, Division of Chemistry, California Institute of Technology, Pasadena, CA 91125;
authors.forename: Nataly
authors.initials: N
authors.lastname: Kravchenko-Balasha
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; youngshik@gmail.com rafi@fh.huji.ac.il heath@caltech.edu.
authors.forename: Young Shik
authors.initials: YS
authors.lastname: Shin
authors.affiliation: NanoSystems Biology Cancer Center, Division of Chemistry, California Institute of Technology, Pasadena, CA 91125;
authors.forename: Alex
authors.initials: A
authors.lastname: Sutherland
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095; The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel youngshik@gmail.com rafi@fh.huji.ac.il heath@caltech.edu.
authors.forename: R D
authors.initials: RD
authors.lastname: Levine
authors.affiliation: NanoSystems Biology Cancer Center, Division of Chemistry, California Institute of Technology, Pasadena, CA 91125; youngshik@gmail.com rafi@fh.huji.ac.il heath@caltech.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Heath
mesh_terms: D002450:Cell Communication; D002465:Cell Movement / Q000502:physiology*; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction; D013816:Thermodynamics
chemical_list: D011506:Proteins
keywords: Brownian dynamics; Langevin equation; cell motility; cell–cell force; surprisal analysis