Connecting signaling and metabolic pathways in EGF receptor-mediated oncogenesis of glioblastoma

PLoS Computational Biology
Arup K BagChitra Mandal

Abstract

As malignant transformation requires synchronization of growth-driving signaling (S) and metabolic (M) pathways, defining cancer-specific S-M interconnected networks (SMINs) could lead to better understanding of oncogenic processes. In a systems-biology approach, we developed a mathematical model for SMINs in mutated EGF receptor (EGFRvIII) compared to wild-type EGF receptor (EGFRwt) expressing glioblastoma multiforme (GBM). Starting with experimentally validated human protein-protein interactome data for S-M pathways, and incorporating proteomic data for EGFRvIII and EGFRwt GBM cells and patient transcriptomic data, we designed a dynamic model for EGFR-driven GBM-specific information flow. Key nodes and paths identified by in silico perturbation were validated experimentally when inhibition of signaling pathway proteins altered expression of metabolic proteins as predicted by the model. This demonstrated capacity of the model to identify unknown connections between signaling and metabolic pathways, explain the robustness of oncogenic SMINs, predict drug escape, and assist identification of drug targets and the development of combination therapies.

References

Aug 2, 1994·Proceedings of the National Academy of Sciences of the United States of America·R NishikawaH J Huang
Dec 11, 1999·Nature·L H HartwellA W Murray
Jul 8, 2000·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·F RévillionJ P Peyrat
Nov 16, 2001·Journal of Theoretical Biology·M W CovertB Palsson
Nov 5, 2002·BMC Bioinformatics·Martin SteffenGeorge Church
Nov 15, 2002·Nature·Hiroaki Kitano
Mar 5, 2004·Biochimica Et Biophysica Acta·Nathalie M Droin, Douglas R Green
May 7, 2004·Nature·Markus W CovertBernhard O Palsson
Jun 23, 2004·Annals of the New York Academy of Sciences·R ChristopherC Hill
Jan 20, 2005·Bioinformatics·Sampsa HautaniemiDouglas A Lauffenburger
Nov 3, 2005·The Journal of Biological Chemistry·Katja BettenbrockErnst-Dieter Gilles
Apr 6, 2006·Proceedings of the National Academy of Sciences of the United States of America·Swaine L ChenJeffrey I Gordon
Apr 28, 2006·Nature Genetics·Michael ReichJill P Mesirov
Jul 11, 2006·Current Opinion in Chemical Biology·Carolyn R ChoManuel C Peitsch
Aug 29, 2006·Drug Discovery Today·Neil KumarDouglas A Lauffenburger
Oct 25, 2006·Nature Cell Biology·Bree B AldridgePeter K Sorger
Dec 7, 2006·Genome Biology·G Traver HartEdward M Marcotte
Apr 7, 2007·Cellular and Molecular Life Sciences : CMLS·E WangM O'Connor-McCourt
Jul 13, 2007·Briefings in Bioinformatics·Claudine Chaouiya
Apr 9, 2008·Oncogene·Z Fu, D J Tindall
Jul 9, 2008·Journal of Molecular Neuroscience : MN·Enrica BodaFilippo Tempia
Aug 7, 2008·Neuro-oncology·Claire Marie-Elisabeth SauvageotPatrick Yung Chih Wen
Mar 10, 2009·FEBS Letters·Andreas ZanzoniPatrick Aloy
Mar 28, 2009·Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia·Hui K GanRodney B Luwor
Jun 10, 2009·Biochimica Et Biophysica Acta·Reinhard LaubenbacherSteven Akman
Jul 16, 2009·Current Molecular Medicine·Saad Z UsmaniZihai Li
Aug 19, 2009·International Journal of Cancer. Journal International Du Cancer·Derek ZiekerAlfred Königsrainer
Sep 10, 2009·Science Signaling·Paul H HuangForest M White
Sep 17, 2009·Genome Medicine·Gilles ClermontMikael Benson
Oct 29, 2009·Carcinogenesis·Pamela K Kreeger, Douglas A Lauffenburger
Nov 13, 2009·Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics·Kartik Anand, Ginestra Bianconi
Jan 14, 2010·Genome Biology·Kumaran KandasamyAkhilesh Pandey
Feb 20, 2010·PloS One·Ethan CeramiChris Sander
Mar 17, 2010·Biochemistry·Melody K MorrisDouglas A Lauffenburger
Aug 3, 2010·BMC Systems Biology·Andrew E Teschendorff, Simone Severini
Sep 14, 2010·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Jacob J HugheyMarkus W Covert
Sep 24, 2010·PLoS Computational Biology·Clare E Giacomantonio, Geoffrey J Goodhill
Sep 30, 2010·Proceedings of the National Academy of Sciences of the United States of America·Sriram Chandrasekaran, Nathan D Price

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Citations

Dec 29, 2020·Frontiers in Genetics·Nupur BiswasSaikat Chakrabarti

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Datasets Mentioned

BETA
ABT-199
GSE53733
GSE50161
GSE36245
GSE15824

Methods Mentioned

BETA
ELISA
light microscopy
PCR

Clinical Trials Mentioned

NCT01606579
NCT01764477
NCT02413853

Software Mentioned

house
PROTEOMESTAT
WebGestalt
Data Analysis
Gene Pattern Expression File Creator
HPPIN
Biotools
NetworkX
Mascot
ImageJ

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