Cell Collective18098000ModelsShannyn Birdhttps://cellcollective.org/#5884/tumour-cell-invasion-and-migration32.4646000000000041SBML1Cell Collectivehttps://cellcollective.org/#5884:1/tumour-cell-invasion-and-migrationUnderstanding the etiology of metastasis is very important in clinical perspective, since it is estimated that metastasis accounts for 90% of cancer patient mortality. Metastasis results from a sequence of multiple steps including invasion and migration. The early stages of metastasis are tightly controlled in normal cells and can be drastically affected by malignant mutations; therefore, they might constitute the principal determinants of the overall metastatic rate even if the later stages take long to occur. To elucidate the role of individual mutations or their combinations affecting the metastatic development, a logical model has been constructed that recapitulates published experimental results of known gene perturbations on local invasion and migration processes, and predict the effect of not yet experimentally assessed mutations. The model has been validated using experimental data on transcriptome dynamics following TGF-β-dependent induction of Epithelial to Mesenchymal Transition in lung cancer cell lines. A method to associate gene expression profiles with different stable state solutions of the logical model has been developed for that purpose. In addition, we have systematically predicted alleviating (masking) and synergistic pairwise genetic interactions between the genes composing the model with respect to the probability of acquiring the metastatic phenotype. We focused on several unexpected synergistic genetic interactions leading to theoretically very high metastasis probability. Among them, the synergistic combination of Notch overexpression and p53 deletion shows one of the strongest effects, which is in agreement with a recent published experiment in a mouse model of gut cancer. The mathematical model can recapitulate experimental mutations in both cell line and mouse models. Furthermore, the model predicts new gene perturbations that affect the early steps of metastasis underlying potential intervention points for innovative therapeutic strategies in oncology.Mathematical Modelling of Molecular Pathways Enabling Tumour Cell Invasion and Migration.Cohen David P A DP, Martignetti Loredana L, Robine Sylvie S, Barillot Emmanuel E, Zinovyev Andrei A, Calzone Laurence Ldp53, Materials, xnotch, Bowel, single-organism developmental process, Metastasis, Laboratory, postnatal development, Mus domesticus, Gene Expression Profile, Neoplasm Metastases, growth and development, Profiles, neoplasm metastasis, Tumor, betaTub3, House Mouse, Tp53, cancer metastasis, Case Fatality Rates, Mutations, Death Rates, Readability, Techniques, Personal, DMP53, NOTCH, Roles, Method, bbl, Line, pathogenesis, Concepts, Dmp53, Excess Mortalities, Fs(3)Hor, notch, average, 1323/07, DmelCG2684, Gene Expressions, reference sample, BCC7, Crude Mortality Rates, Moods, long, beta-Tub6D, dmp53, alimentary tract, T, DmP53, 1422/04, Swiss Mice, Ax, NTef2, Estimated, Signatures, genetic, B3t, DmelCG3401, notch1-a, g, Methodological Studies, malignant neoplasm, Expression Signature, Dp53, CFR Case Fatality Rate, co, Role Concepts, Xotch, Transcriptomes, asd, Malignancies, house mouse, Age-Specific Death Rate, CG17117, adult alimentary canal, alimentary system, NECD, EG:140G11.1, p50/tubulin, l(1)N, Tumors, swb, CG10873, anatomical protrusion, PLATEST, Chp, Co, Expression Profiles, familial, mouse, Crude Death, Procedure, maskin, results, predicted, Crude Mortality, Fs(3)Sz11, 3t, Gene Expression, Mortality, Benign, Role Concept, Expression Signatures, EMT, shd, Role, Genetic Materials, bfy, Expression Profile, fa, Genetic Material, Tub60D, HTH, Hth, Transcriptome Profiles, Lines, xnotch1, Mus musculus, beta-tub, AI747421, death rate, mice, Dignity, DmelCG33336, Swiss Mouse, CG3401, Benign Neoplasms, Mortalities, beta3Tub, beta3TUB, INSDC_feature:gene, Methodological, Methodological Study, early, Malignant Neoplasms, experimental procedures, domesticus, DTB3, Phenotypes, metastatic, hth1, Mortality Rate, Crude Death Rate, hth2, Patient, clone 1.12, Material, spine, gastrointestinal system, Horka, P53, CG2684, Fs(3)Horka, xmaskin, p44, bhy, Cistron, inherited genetic, notch-1, Mouse, Mortality Determinant, TAN1, n[fah], CG31325, Platelets, betaTub, beta[[3]]-Tub, digestive canal, DmelCG17117, Respect, Procedures, experimental, p50, Transcriptome Profile, Mortality Declines, Neoplasms, p53, Benign Neoplasm, EG:163A10.2, Excess, Gene, 143391_i_at, beta3 TU, Crude Mortality Rate, Malignant, mortality measurement, LFS1, l(3)05745, Age-Specific Death, protrusion, Intervention or Procedure, Mortality Determinants, Crude, method, Gus, Gur, Rate, Determinant, Gut, House, method used in an experiment, Studies, Mus musculus domesticus, Case Fatality, Mood, DmF2, l(1)3Cb, anon-EST:Liang-2.13, Mice, Technique, l(1)Ax, lod, Differential Mortality, tumor cell migration, Excess Mortality, methods, gut, Genetic, clone 2.13, Malignancy, interventionDescription, Swiss, experimental section, D.m.BETA-60D, Profile, DmelCG3936, Interventional, metastasis, causes, dNotch, Age-Specific, epithelial-mesenchymal transition, Expressions, Solution, Probabilities, Neoplasias, Study, masking, Trp53, SURGICAL AND MEDICAL PROCEDURES., Clients, Personal Respect, Mortality Rates, causality, mortality rate, betaTub60C, Crude Death Rates, mesenchymal cell differentiation from epithelial cell, beta3-tubulin, Expression, beta[[3]]-tubulin, TRP53, NICD, constitutitional genetic, Age Specific Death Rate, tumor metastasis, CT13012, intestines, Controlled, Cancer, 16-178, beta-Tub60D, Intervention Strategies, 16-55, Controlling, Dmbeta3, Transcriptome, Dm-HTH, Malignant Neoplasm, Mortality Decline, Affects, Metastases, BETA 60D, prac, beta3t, beta3-Tub, Cell Lines, anon-EST:Liang-1.12, Cistrons, Client, Cell, Xp53, Concept, Metastase, development, Case Fatality Rate, gut tube, Experiment, MT, survival, Mus, p53/tubulin, Gene Expression Signatures, spl, Neoplasm, sequence, 1.1, Gene Expression Signature, nd, beta[[3]] tubulin, Determinants, Death, Intervention, Rates, CG33336, Death Rate, primary cancer, postnatal growth, D-p53, beta60C, Gus-u, Gus-t, Gus-s, Dm-P53, l(3)86Ca, House Mice, Gus-r, patient, Cancers, beta3, Understanding, Age-Specific Death Rates, Lds, malignant tumor, primary structure of sequence macromolecule, dtl, Laboratory Mice, plan specification, Tub, Meis1, Differential, DEL, Gene Expression Profiles, betatub60D, Decline, Signature, CG3936, growth, hereditary, Laboratory Mouse, Neoplasia, Differential Mortalitiestumor cell., tumour celltumor cell., tumour celldp53, Materials, xnotch, Bowel, single-organism developmental process, Metastasis, Laboratory, Theoretical Model, postnatal development, Mus domesticus, Gene Expression Profile, Neoplasm Metastases, growth and development, Profiles, neoplasm metastasis, Tumor, betaTub3, House Mouse, Tp53, cancer metastasis, Mathematical Models, Case Fatality Rates, Mutations, Death Rates, Readability, Techniques, Personal, DMP53, NOTCH, Roles, Method, bbl, Line, pathogenesis, 10.5, Concepts, Dmp53, Excess Mortalities, Fs(3)Hor, lung carcinoma cell, notch, 10.9, average, 1323/07, DmelCG2684, F, Theoretical Study, Gene Expressions, reference sample, DmelCG2328, BCC7, Crude Mortality Rates, Moods, long, beta-Tub6D, dmp53, alimentary tract, T, DmP53, 1422/04, Swiss Mice, V, Ax, NTef2, Estimated, Signatures, SURGICAL AND MEDICAL PROCEDURES, genetic, B3t, DmelCG3401, notch1-a, g, Methodological Studies, malignant neoplasm, Expression Signature, Dp53, CFR Case Fatality Rate, co, Role Concepts, Xotch, Transcriptomes, Therapies, asd, Malignancies, house mouse, Age-Specific Death Rate, CG17117, adult alimentary canal, alimentary system, NECD, EG:140G11.1, p50/tubulin, l(1)N, Tumors, swb, Therapy, CG10873, anatomical protrusion, PLATEST, Chp, Co, Expression Profiles, familial, mouse, Crude Death, Procedure, maskin, results, predicted, Crude Mortality, Fs(3)Sz11, 3t, Gene Expression, Mortality, Experimental, Benign, Role Concept, Expression Signatures, EMT, shd, Theoretical Studies, Role, Genetic Materials, VI, bfy, Expression Profile, fa, Genetic Material, Tub60D, HTH, Hth, Transcriptome Profiles, Lines, xnotch1, Mus musculus, beta-tub, 20.35, AI747421, death rate, mice, Dignity, DmelCG33336, Swiss Mouse, CG3401, Benign Neoplasms, Mortalities, beta3Tub, beta3TUB, INSDC_feature:gene, Methodological, Methodological Study, early, Malignant Neoplasms, domesticus, Theoretical Models, DTB3, Phenotypes, metastatic, hth1, Mortality Rate, Crude Death Rate, hth2, Patient, clone 1.12, Material, spine, gastrointestinal system, Horka, P53, CG2684, Fs(3)Horka, eve2, xmaskin, p44, bhy, Cistron, inherited genetic, notch-1, Mouse, Mortality Determinant, TAN1, n[fah], CG31325, Mathematical Model, Platelets, betaTub, CG2328, 14.10, beta[[3]]-Tub, digestive canal, DmelCG17117, Respect, Procedures, p50, Transcriptome Profile, Experimental Models, Mortality Declines, Neoplasms, p53, Benign Neoplasm, EG:163A10.2, Excess, Gene, 143391_i_at, beta3 TU, Crude Mortality Rate, Malignant, mortality measurement, LFS1, l(3)05745, Theoretical, Age-Specific Death, protrusion, Intervention or Procedure, Mortality Determinants, Crude, method, Gus, Gur, Rate, Determinant, Gut, House, method used in an experiment, Studies, Mus musculus domesticus, Case Fatality, Experimental Model, Mood, DmF2, even, l(1)3Cb, anon-EST:Liang-2.13, Mice, Models, Technique, l(1)Ax, lod, Differential Mortality, tumor cell migration, Excess Mortality, gut, Genetic, clone 2.13, Malignancy, interventionDescription, Swiss, D.m.BETA-60D, Profile, DmelCG3936, Interventional, metastasis, Treatments., causes, dNotch, Age-Specific, Theoretic, epithelial-mesenchymal transition, Expressions, Solution, Probabilities, Neoplasias, Study, masking, Trp53, Mathematical, Clients, Personal Respect, Mortality Rates, causality, mortality rate, betaTub60C, Crude Death Rates, mesenchymal cell differentiation from epithelial cell, beta3-tubulin, Expression, beta[[3]]-tubulin, TRP53, NICD, Model, constitutitional genetic, Age Specific Death Rate, tumor metastasis, CT13012, intestines, Controlled, Cancer, 16-178, beta-Tub60D, Intervention Strategies, 16-55, Controlling, Dmbeta3, Transcriptome, Dm-HTH, Malignant Neoplasm, Mortality Decline, Affects, Metastases, BETA 60D, prac, beta3t, beta3-Tub, Cell Lines, Model (Theoretical), anon-EST:Liang-1.12, Cistrons, Client, Cell, Xp53, Concept, Metastase, development, Case Fatality Rate, gut tube, Experiment, MT, survival, Mus, p53/tubulin, Gene Expression Signatures, spl, Neoplasm, sequence, 1.1, Eve, EVE, Gene Expression Signature, nd, beta[[3]] tubulin, Determinants, Death, Intervention, Rates, CG33336, Death Rate, primary cancer, postnatal growth, D-p53, beta60C, Gus-u, l(2)46Ce, Gus-t, Gus-s, Dm-P53, l(3)86Ca, House Mice, Gus-r, patient, Cancers, beta3, Understanding, Age-Specific Death Rates, Lds, malignant tumor, primary structure of sequence macromolecule, l(2)46Cg, dtl, Laboratory Mice, l(2)46CFj, plan specification, Tub, l(2)46CFh, Meis1, Differential, Models (Theoretical), Therapeutic, l(2)46CFp, DEL, Gene Expression Profiles, betatub60D, Decline, Treatment, Signature, CG3936, E(eve), growth, hereditary, Laboratory Mouse, Neoplasia, Differential Mortalities, l(2)46CFg18098falseTumour Cell Invasion and MigrationUnderstanding the etiology of metastasis is very important in clinical perspective, since it is estimated that metastasis accounts for 90% of cancer patient mortality. Metastasis results from a sequence of multiple steps including invasion and migration. The early stages of metastasis are tightly controlled in normal cells and can be drastically affected by malignant mutations; therefore, they might constitute the principal determinants of the overall metastatic rate even if the later stages take long to occur. To elucidate the role of individual mutations or their combinations affecting the metastatic development, a logical model has been constructed that recapitulates published experimental results of known gene perturbations on local invasion and migration processes, and predict the effect of not yet experimentally assessed mutations. The model has been validated using experimental data on transcriptome dynamics following TGF--dependent induction of Epithelial to Mesenchymal Transition in lung cancer cell lines. A method to associate gene expression profiles with different stable state solutions of the logical model has been developed for that purpose. In addition, we have systematically predicted alleviating (masking) and synergistic pairwise genetic interactions between the genes composing the model with respect to the probability of acquiring the metastatic phenotype. We focused on several unexpected synergistic genetic interactions leading to theoretically very high metastasis probability. Among them, the synergistic combination of Notch overexpression and p53 deletion shows one of the strongest effects, which is in agreement with a recent published experiment in a mouse model of gut cancer. The mathematical model can recapitulate experimental mutations in both cell line and mouse models. Furthermore, the model predicts new gene perturbations that affect the early steps of metastasis underlying potential intervention points for innovative therapeutic strategies in oncology.2017-02-012017-04-282017-04-28588426528548