Fey, Dirk ORCID: 0000-0002-5558-0167, Halasz, Melinda ORCID: 0000-0002-6175-9630, Dreidax, Daniel, Kennedy, Sean P., Hastings, Jordan F., Rauch, Nora ORCID: 0000-0001-6009-5177, Munoz, Amaya Garcia, Pilkington, Ruth, Fischer, Matthias, Westermann, Frank, Kolch, Walter ORCID: 0000-0001-5777-5016, Kholodenko, Boris N. and Croucher, David R. (2015). Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients. Sci. Signal., 8 (408). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1937-9145

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Abstract

Signaling pathways control cell fate decisions that ultimately determine the behavior of cancer cells. Therefore, the dynamics of pathway activity may contain prognostically relevant information different from that contained in the static nature of other types of biomarkers. To investigate this hypothesis, we characterized the network that regulated stress signaling by the c-Jun N-terminal kinase (JNK) pathway in neuroblastoma cells. We generated an experimentally calibrated and validated computational model of this network and used the model to extract prognostic information from neuroblastoma patient-specific simulations of JNK activation. Switch-like JNK activation mediates cell death by apoptosis. An inability to initiate switch-like JNK activation in the simulations was significantly associated with poor overall survival for patients with neuroblastoma with or without MYCN amplification, indicating that patient-specific simulations of JNK activation could stratify patients. Furthermore, our analysis demonstrated that extracting information about a signaling pathway to develop a prognostically useful model requires understanding of not only components and disease-associated changes in the abundance or activity of the components but also how those changes affect pathway dynamics.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fey, DirkUNSPECIFIEDorcid.org/0000-0002-5558-0167UNSPECIFIED
Halasz, MelindaUNSPECIFIEDorcid.org/0000-0002-6175-9630UNSPECIFIED
Dreidax, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kennedy, Sean P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hastings, Jordan F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauch, NoraUNSPECIFIEDorcid.org/0000-0001-6009-5177UNSPECIFIED
Munoz, Amaya GarciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pilkington, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Westermann, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolch, WalterUNSPECIFIEDorcid.org/0000-0001-5777-5016UNSPECIFIED
Kholodenko, Boris N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Croucher, David R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-383580
DOI: 10.1126/scisignal.aab0990
Journal or Publication Title: Sci. Signal.
Volume: 8
Number: 408
Date: 2015
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1937-9145
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NEGATIVE FEEDBACK; INDUCED APOPTOSIS; EXPRESSION; ACTIVATION; PROTEIN; CELLS; MYCN; MAPK; PHOSPHORYLATION; TRANSDUCTIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/38358

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