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Intercellular signaling through secreted proteins induces free-energy gradient-directed cell movement

Kravchenko-Balasha, Nataly and Shin, Young Shik and Sutherland, Alex and Levine, R. D. and Heath, James R. (2016) Intercellular signaling through secreted proteins induces free-energy gradient-directed cell movement. Proceedings of the National Academy of Sciences of the United States of America, 113 (20). pp. 5520-5525. ISSN 0027-8424. PMCID PMC4878481.

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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.

Item Type:Article
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URLURL TypeDescription Information CentralArticle
Heath, James R.0000-0001-5356-4385
Additional Information:© 2016 National Academy of Sciences. Edited by Michael L. Klein, Temple University, Philadelphia, PA, and approved March 31, 2016 (received for review February 8, 2016). Published online before print May 2, 2016. We acknowledge helpful discussions with Dr. David A. Nathanson and Lisa Ta. This work was funded by National Cancer Institute Grant 1U54CA199090-01 [to J.R.H., principal investigator (PI)], the Ben and Catherine Ivy Foundation (J.R.H.), the Jean Perkins Foundation (J.R.H., PI), the Korean-American Scientists and Engineers Association (Y.S.S., PI), the Phelps Family Foundation (Y.S.S.), and European Commission FP7 Future and Emerging Technologies–Open Project BAMBI 618024 (to R.D.L.). N.K.-B. was supported by an EMBO postdoctoral fellowship. Author contributions: N.K.-B., Y.S.S., R.D.L., and J.R.H. designed research; N.K.-B. performed theoretical research; Y.S.S. performed experimental research; N.K.-B., Y.S.S., A.S., R.D.L., and J.R.H. contributed new reagents/analytic tools; N.K.-B., Y.S.S., R.D.L., and J.R.H. analyzed data; and N.K.-B., Y.S.S., R.D.L., and J.R.H. wrote the paper. N.K.-B. and Y.S.S. contributed equally to this work. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at
Funding AgencyGrant Number
National Cancer Institute1U54CA199090-01
Ben and Catherine Ivy FoundationUNSPECIFIED
Jean Perkins FoundationUNSPECIFIED
Korean-American Scientists and Engineers AssociationUNSPECIFIED
Phelps Family FoundationUNSPECIFIED
European Research Council (ERC)BAMBI 618024
European Molecular Biology Organization (EMBO)UNSPECIFIED
Subject Keywords:cell–cell force; cell motility; surprisal analysis; Langevin equation; Brownian dynamics
Issue or Number:20
PubMed Central ID:PMC4878481
Record Number:CaltechAUTHORS:20160503-072858145
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Official Citation:Nataly Kravchenko-Balasha, Young Shik Shin, Alex Sutherland, R. D. Levine, and James R. Heath Intercellular signaling through secreted proteins induces free-energy gradient-directed cell movement PNAS 2016 113 (20) 5520-5525; published ahead of print May 2, 2016, doi:10.1073/pnas.1602171113
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66602
Deposited By: Tony Diaz
Deposited On:03 May 2016 15:06
Last Modified:03 Oct 2019 09:58

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