title: Advances in dynamic modeling of colorectal cancer signaling-network regions, a path toward targeted therapies.
abstract: The interconnected network of pathways downstream of the TGFβ, WNT and EGF-families of receptor ligands play an important role in colorectal cancer pathogenesis.We studied and implemented dynamic simulations of multiple downstream pathways and described the section of the signaling network considered as a Molecular Interaction Map (MIM). Our simulations used Ordinary Differential Equations (ODEs), which involved 447 reactants and their interactions.Starting from an initial "physiologic condition", the model can be adapted to simulate individual pathologic cancer conditions implementing alterations/mutations in relevant onco-proteins. We verified some salient model predictions using the mutated colorectal cancer lines HCT116 and HT29. We measured the amount of MYC and CCND1 mRNAs and AKT and ERK phosphorylated proteins, in response to individual or combination onco-protein inhibitor treatments. Experimental and simulation results were well correlated. Recent independently published results were also predicted by our model.Even in the presence of an approximate and incomplete signaling network information, a predictive dynamic modeling seems already possible. An important long term road seems to be open and can be pursued further, by incremental steps, toward even larger and better parameterized MIMs. Personalized treatment strategies with rational associations of signaling-proteins inhibitors, could become a realistic goal.
authors: Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Italy.
authors: Lorenzo
authors: L
authors: Tortolina
authors: Systems Biology Ireland, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors: David J
authors: DJ
authors: Duffy
authors: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Italy.
authors: Massimo
authors: M
authors: Maffei
authors: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Italy.
authors: Nicoletta
authors: N
authors: Castagnino
authors: Systems Biology Ireland, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors: Aimée M
authors: AM
authors: Carmody
authors: Systems Biology Ireland, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors: Walter
authors: W
authors: Kolch
authors: Systems Biology Ireland, Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors: Boris N
authors: BN
authors: Kholodenko
authors: Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Italy.
authors: Cristina
authors: C
authors: De Ambrosi
authors: Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Italy.
authors: Annalisa
authors: A
authors: Barla
authors: Unit of Medical Statistics, Biometry and Bioinformatics "Giulio A. Maccacaro", Department of Clinical Sciences and Community Health, University of Milan, Italy.
authors: Elia M
authors: EM
authors: Biganzoli
authors: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Italy.|Istituto a Carattere di Ricerca Clinic - Scientifico (IRCCS), Azienda Ospedaliera Universitaria San Martino, Istituto Nazionale Tumori (IST), Genoa, Italy.
authors: Alessio
authors: A
authors: Nencioni
authors: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Italy.|Istituto a Carattere di Ricerca Clinic - Scientifico (IRCCS), Azienda Ospedaliera Universitaria San Martino, Istituto Nazionale Tumori (IST), Genoa, Italy.
authors: Franco
authors: F
authors: Patrone
authors: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Italy.|Istituto a Carattere di Ricerca Clinic - Scientifico (IRCCS), Azienda Ospedaliera Universitaria San Martino, Istituto Nazionale Tumori (IST), Genoa, Italy.
authors: Alberto
authors: A
authors: Ballestrero
authors: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Italy.|Istituto a Carattere di Ricerca Clinic - Scientifico (IRCCS), Azienda Ospedaliera Universitaria San Martino, Istituto Nazionale Tumori (IST), Genoa, Italy.
authors: Gabriele
authors: G
authors: Zoppoli
authors: Department of Informatics, Bioengineering, Robotics and Systems Engineering (DIBRIS), University of Genoa, Italy.
authors: Alessandro
authors: A
authors: Verri
authors: Department of Internal Medicine and Medical Specializations (DIMI), University of Genoa, Italy.
authors: Silvio
authors: S
authors: Parodi
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology
chemical_list: D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor
keywords: colorectal cancer; dynamic modeling; onco-protein inhibitors; signaling-network; target therapies