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Published April 29, 2014 | Supplemental Material + Published
Journal Article Open

Glioblastoma cellular architectures are predicted through the characterization of two-cell interactions


To understand how pairwise cellular interactions influence cellular architectures, we measured the levels of functional proteins associated with EGF receptor (EGFR) signaling in pairs of U87EGFR variant III oncogene receptor cells (U87EGFRvIII) at varying cell separations. Using a thermodynamics-derived approach we analyzed the cell-separation dependence of the signaling stability, and identified that the stable steady state of EGFR signaling exists when two U87EGFRvIII cells are separated by 80–100 μm. This distance range was verified as the characteristic intercellular separation within bulk cell cultures. EGFR protein network signaling coordination for the U87EGFRvIII system was lowest at the stable state and most similar to isolated cell signaling. Measurements of cultures of less tumorigenic U87PTEN cells were then used to correctly predict that stable EGFR signaling occurs for those cells at smaller cell–cell separations. The intimate relationship between functional protein levels and cellular architectures explains the scattered nature of U87EGFRvIII cells relative to U87PTEN cells in glioblastoma multiforme tumors.

Additional Information

© 2014 National Academy of Sciences. Contributed by R. D. Levine, March 13, 2014 (sent for review November 21, 2013). We thank Alexander Levitzki and Ayelet Lesman for valuable discussions. Financial support was provided by National Cancer Institute Grant 5U54 CA119347 (to J.R.H.), the Jean Perkins Foundation, the Ben and Catherine Ivy Foundation, and European Commission FP7 Future and Emerging Technologies-Open Project BAMBI 618024 (to F.R. and R.D.L.). N.K.-B. is the recipient of a European Molecular Biology Organization Long-Term Fellowship. F.R. is Director of Fonds National de la Recherche Scientifique, Belgium. N.K.B. and J.W. contributed equally to this work. Author contributions: N.K.-B., R.D.L., and J.R.H. designed research; J.W. designed and performed experimental research; N.K.-B. performed experimental and theoretical research; N.K.-B., R.D.L., and J.R.H. contributed new reagents/analytic tools; N.K.-B., J.W., F.R., R.D.L., and J.R.H. analyzed data; and N.K.-B., F.R., R.D.L., and J.R.H. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1404462111/-/DCSupplemental.

Attached Files

Published - PNAS-2014-Kravchenko-Balasha-6521-6.pdf

Supplemental Material - PNAS-2014-Kravchenko-Balasha-1404462111_SI.pdf


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