Cell CollectiveModelsAudrey Crowtherhttps://cellcollective.org/#4601/colitisassociated-colon-cancer82.409600000000011SBML1Cell Collectivehttps://cellcollective.org/#4601:1/colitisassociated-colon-cancerThe connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner.Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.Lu Junyan J, Zeng Hanlin H, Liang Zhongjie Z, Chen Limin L, Zhang Liyi L, Zhang Hao H, Liu Hong H, Jiang Hualiang H, Shen Bairong B, Huang Ming M, Geng Meiyu M, Spiegel Sarah S, Luo Cheng Cl(3)rK137, dp53, PRKBA, Akt/PKB, malignant neoplasm of colon, Inflammations, Epithelial Cell, single-organism developmental process, DAKT1/PKB, postnatal development, growth and development, Colon Cancer, AKT1, Glandular, Tumor, betaTub3, CG17228, Tp53, 1135/09, 1135/07, malignant colonic neoplasm, Donor Artificial Insemination, DMP53, Taenia Coli, bbl, CDA2, Appendix, 0451/09, malignant tumor of colon, Impacts, Dmp53, Environmental Impacts, malignant tumor of the colon, Donor Artificial, 1323/07, Omental Appendix, 0244/09, inflammatory response, BCC7, MUB3_18, beta-Tub6D, dmp53, DROPROSA, T, DmP53, 1422/04, Colonic Cancer, Adenomatous Epithelial, MUB3.18, l(3)j6E2, PKB|Akt, large intestine cancer, RacPK, 671/2, Environmental Impact, B3t, DmelCG3401, 0320/10, DMPROSPER, Dp53, malignant neoplasm, malignant neoplasm of the colon, Malignancies, cancer of colon, associated, CG17117, somatic mutation, p50/tubulin, Tumors, Transitional Epithelial Cell, CG10873, dakt, l(3)rO534, PRO, Pro, inflammation of colon, Adenomatous, Colon Adenocarcinoma, Squamous, l(3)89Bq, Appendix Epiploica, Transitional Epithelial, Adenocarcinomas, CYS, 3t, PKB/Akt, PKB/AKT, AKT/PKB, Colonic Cancers, PROS-1, PROS-2, Benign, dAkt, dAKT, p53-binding protein Mdm2, pro, 1316/02, Heterologous Insemination, malignant colonic tumor, p-Akt, BcDNA:HL08040, bfy, DAkt, Omental Appendices, and GLY protein 2, Tub60D, HTH, Hth, l(3)04226, Adenomatous Epithelial Cell, beta-tub, DPKB, Adenomatous Epithelial Cells, Squamous Cell, and GLY protein 1, pAkt, Voila, susceptibility to, 0664/07, DmelCG33336, 1167/13, CG3401, double minute 2 protein, beta3Tub, beta3TUB, Appendices, Benign Neoplasms, Colon, dAKT/dPKB, PKB/dAKT, TAF[[II]], Malignant Neoplasms, DTB3, Artificial Insemination, hth1, Cancer of Colon, Dakt, hth2, COLON, dPKB, Cells, P53, p44, bhy, l(1)16Fg, 0989/01, other neoplasm, malignant colon neoplasm, Innate, CG31325, betaTub, RAC-ALPHA, pds, Malignant Neoplasms., Adenocarcinoma, beta[[3]]-Tub, colon tumor, DRAC-PK85, Colon Neoplasm, Inflammatory Response, DmelCG17117, DmelCG4006, p50, ACTFS, Colon Adenocarcinomas, Neoplasms, p53, Benign Neoplasm, 143391_i_at, beta3 TU, Glandular Epithelial, LFS1, 0763/13, Malignant, autosomal dominant, AID, Aid, l(3)05745, l(3)10419, colon neoplasm, Dpkb, dmTAF8, Squamous Epithelial Cells, DmelCG17228, 1700007J15Rik, HL-VIII, Colon Neoplasms, malignant tumour of colon, anon-WO0140519.15, F15E12.6, colon inflammation, Prosp, anon-EST:Liang-2.13, Squamous Epithelial, aid, malignant colon tumour, Epithelial, Insemination, RING-type E3 ubiquitin transferase Mdm2, PROS, F15E12_6, 0585/13, Colonic, clone 2.13, Malignancy, D.m.BETA-60D, hdm2, CG7128, posterior intestine, inflammation, Cancer of the Colon, l(3)rH013, Neoplasias, malignant colon tumor, malignant colonic tumour, prod, Trp53, Prodos, Innate Inflammatory Response, AKT, Epithelial Cells, Akt, Transitional Epithelial Cells, HEL-S-284, betaTub60C, DRAC-PK, beta3-tubulin, HIGM2, beta[[3]]-tubulin, TRP53, MDM2, TAF, 0563/18, Colitides, Squamous Epithelial Cell, Glandular Epithelial Cell, Heterologous, Cancer, 0671/02, Transitional, beta-Tub60D, l(3)j12C8, colitis, oncoprotein Mdm2, Squamous Cells, Dmbeta3, HDMX, Dm-HTH, Malignant Neoplasm, akt, malignant, BETA 60D, prac, beta3t, beta3-Tub, DAkt1, DAKT1, hindgut, Cell, Xp53, l(3)rJ806, Pros, Impact, Human Donor, development, Environmental, colitis (disease), l(3)rL433, PKB, MT, CWS6, Cuboidal Glandular Epithelial Cells, l(3)rI160, 0441/16, p53/tubulin, PKB-ALPHA, Neoplasm, core, D-Akt, TFIID, CG4006, Donor, CRC, Columnar Glandular Epithelial Cells, beta[[3]] tubulin, ATCMPG1, MET, ATCMPG2, Dakt1, Artificial, CG33336, Colon Cancers, primary cancer, akt1, dAkt1, Arp2, ARP2, DRAC-PK66, postnatal growth, Colonic Neoplasm, D-p53, beta60C, Colon cancer, Glandular Epithelial Cells, AA415488, Dm-P53, l(3)86Ca, Cancers, beta3, Mdm-2, Omental, malignant tumor, dtl, Tub, l(3)rK204, Meis1, dAkt/PKB, dakt1, colon cancer, DmelCG7128, betatub60D, Innate Inflammatory Responses, malignant tumour of the colon, PKBalpha, Environments, dAKT1, RAC, Rac, TAF8, growth, NeoplasiaAdenocarcinoma, colon tumor, colitis, Colon Neoplasm, malignant neoplasm of colon, Malignant Neoplasm, Colon Adenocarcinomas, malignant, Neoplasms, Benign Neoplasm, inflammation of colon, Colon Cancer, Colon Adenocarcinoma, Tumor, Malignant, Adenocarcinomas, autosomal dominant, colon neoplasm, malignant colonic neoplasm, colitis (disease), Colonic Cancers, MT, 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of the Colon, Colon Adenocarcinoma, Colon, Adenocarcinomas, autosomal dominant, large intestine cancer, colon neoplasm, malignant colon tumor, malignant colonic tumour, malignant colonic neoplasm, malignant colon tumour., colitis (disease), Colonic Cancers, colon cancer, Cancer of Colon, malignant tumour of the colon, malignant neoplasm of the colon, Neoplasm, Colon Neoplasms, malignant tumor of colon, malignant colonic tumor, malignant tumour of colon, CRC, colon inflammation, cancer of colon, associated, Colitides, malignant colon neoplasm, somatic mutation, malignant tumor of the colon, Cancerdp53, PRKBA, Akt/PKB, nucleocytoplasm, malignant neoplasm of colon, dP60, Product, Vps34, DAKT1/PKB, BcDNA:LD15217, growth and development, Colon Cancer, Glandular, AKT1, Tumor, CG17228, VPS34, 11621, 1135/09, Mutations, PI-3 kinase, 1135/07, p110-alpha, malignant colonic neoplasm, bbl, Appendix, 0451/09, Cer, malignant tumor of colon, 0244/09, Dp60, BCC7, PI3K_59F, beta-Tub6D, dmp53, DROPROSA, T, 1422/04, PI3-kinase activity, Adenomatous Epithelial, PI3Kgamma, RacPK, 671/2, MCAP, Dp53, medicine, PI3K 68D, cancer of colon, CG17117, p50/tubulin, ATP - 1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, single organism signaling, 5848, Tumors, Diagnostic Findings, close to, Carbonate dehydratase II, CG10873, dVps34, anatomical protrusion, rea, p50alpha, Squamous, Appendix Epiploica, CG2699, CG5848, DmelCG5373, AKT/PKB, Benign, C530050K14, 1316/02, type-1 PI3K, HEL-76, p-Akt, BcDNA:HL08040, bfy, Omental Appendices, HTH, Hth, CG11621, Adenomatous Epithelial Cells, 1167/13, CG3401, beta3Tub, beta3TUB, Benign Neoplasms, Colon, dAKT/dPKB, PKB/dAKT, DmelCG4141, F8A5_4, Malignant Neoplasms, APDS, DTB3, BG:DS02740.15, COLON, PI3KBETA, Cells, bhy, l(1)16Fg, 0989/01, other neoplasm, Innate, Clinical Finding, CG31325, RAC-ALPHA, pds, Adenocarcinoma, beta[[3]]-Tub, DmelCG17117, DmelCG4006, Neoplasms, ceramides, 143391_i_at, beta3 TU, LFS1, 0763/13, l(3)05745, dip6, PIK3, DmelCG17228, dVps34/PI3K59F, Pi3Kp60, PI3K-dp110, malignant tumour of colon, dPI3K, anon-92Ed, Prosp, anon-EST:Liang-2.13, class I, RING-type E3 ubiquitin transferase Mdm2, F15E12_6, CACT, posterior intestine, inflammation, Pi3Kp110, nct, l(3)rH013, P110BETA, Neoplasias, malignant colonic tumour, Prodos, drugs, PI3K21B, Innate Inflammatory Response, AKT, Transitional Epithelial Cells, Akt, Cact, beta[[3]]-tubulin, MCM, MDM2, Cancer, 0671/02, Cpk, Pharmaceuticals, Transitional, l(3)j12C8, Products, Squamous Cells, colitis, Cpo, oncoprotein Mdm2, Dmbeta3, Malignant Neoplasm, AA414921, CPX, akt, class II, type III phosphoinositide 3-kinase activity, prac, beta3t, DAkt1, DAKT1, Cell, hindgut, PI(3)K, cpk, near to, PI3K-92E/Dp110, l(3)rL433, PIK3C1, PKB, MT, Cuboidal Glandular Epithelial Cells, CWS6, l(3)rI160, 0441/16, CWS5, p53/tubulin, PKB-ALPHA, Neoplasm, CG4006, fs(2)ltoRN48, CRC, Columnar Glandular Epithelial Cells, ATCMPG1, MET, ATCMPG2, Dakt1, Carbonic anhydrase II, CG33336, Colon Cancers, primary cancer, Pharmaceutic Preparations, postnatal growth, Colonic Neoplasm, D-p53, Dm-P53, Cancers, beta3, Mdm-2, Omental, DmelCG11621, Understanding, malignant tumor, dtl, signalling, Tub, l(3)rK204, CAII, extracellular, caPI3K, dAkt/PKB, colon cancer, CLOVE, signalling process, DmVps34, betatub60D, IMD14, PI3K_68D, PI3K-92D, vicinity of, Dmp110, Pharmaceutical Products, Neoplasia, l(3)rK137, Inflammations, Epithelial Cell, CG5373, single-organism developmental process, ATVPS34, postnatal development, PI3K, Dp110, Ceramide, betaTub3, Tp53, Readability, PHOSPHATIDYLINOSITOL 3-KINASE, DMP53, DmelCG5848, DmelCG2699, F8A5.4, Taenia Coli, Pharmaceutical Product, p110alpha, Dmp53, phosphatidylinositol 3-kinase activity, malignant tumor of the colon, 1323/07, Omental Appendix, inflammatory response, MUB3_18, Pi3K92D, CG4141, catalyst activity, Pi3k, DmP53, Colonic Cancer, MUB3.18, l(3)j6E2, PI[[3]]K, PKB|Akt, large intestine cancer, B3t, DmelCG3401, 0320/10, DMPROSPER, p55alpha, malignant neoplasm, Pharmaceutical, signaling process, malignant neoplasm of the colon, Therapies, Malignancies, Pi3K, PI3k, associated, MCMTC, somatic mutation, Transitional Epithelial Cell, Therapy, SIGNS SYMPTOMS, PI3K68D, dakt, l(3)rO534, PRO, Pro, P110DELTA, PtdIns-3-kinase activity, DESC, inflammation of colon, Adenomatous, Colon Adenocarcinoma, l(3)89Bq, Transitional Epithelial, Adenocarcinomas, CYS, vacuolar protein sorting 34, dPIK, 1-phosphatidylinositol 3-kinase activity, 3t, PKB/Akt, PKB/AKT, Colonic Cancers, PROS-1, PROS-2, dAkt, dAKT, p53-binding protein Mdm2, pro, Carbonic anhydrase C, N-acylated sphingoid, malignant colonic tumor, HCP, Pharmaceutic, internal to cell, DAkt, and GLY protein 2, Tub60D, l(3)04226, Adenomatous Epithelial Cell, beta-tub, DPKB, Epistemology, Squamous Cell, and GLY protein 1, pAkt, Voila, p85alpha, susceptibility to, 0664/07, a ceramide, DmelCG33336, double minute 2 protein, Appendices, PI3K 68_D, TAF[[II]], Treatments, Car2, hth1, p110D, Cancer of Colon, Dakt, hth2, spine, dPKB, P53, p44, p120-PI3K, malignant colon neoplasm, droPIK57, betaTub, Malignant Neoplasms., colon tumor, DRAC-PK85, Inflammatory Response, Colon Neoplasm, biological signaling, p50, ACTFS, Colon Adenocarcinomas, PI3K92E, p53, Benign Neoplasm, Pi3K_59F, Glandular Epithelial, type I phosphatidylinositol kinase activity, Malignant, autosomal dominant, Symptoms and Signs, phosphatidylinositol 3-kinase, protrusion, l(3)10419, colon neoplasm, CA-II, Dpkb, dmTAF8, Squamous Epithelial Cells, p60, 1700007J15Rik, HL-VIII, Colon Neoplasms, anon-WO0140519.15, F15E12.6, PHOSPATIDYLINOSITOL 3-KINASE, colon inflammation, Finding, Squamous Epithelial, Dp110/PI3K, Epithelial, malignant colon tumour, PI3K-68D/E, protoplasm, Drugs, PROS, 0585/13, Colonic, clone 2.13, protoplast, Malignancy, D.m.BETA-60D, n(2)k17003, hdm2, CG7128, PI3'K, Cancer of the Colon, malignant colon tumor, prod, PI3K-68D, Trp53, Epithelial Cells, betaTub60C, DRAC-PK, beta3-tubulin, TRP53, Preparation, TAF, 0563/18, Squamous Epithelial Cell, Colitides, Glandular Epithelial Cell, beta-Tub60D, dP110, HDMX, Dm-HTH, 6330412C24Rik, p120, malignant, BETA 60D, beta3-Tub, p110, Vps34p, Medications, Xp53, l(3)rJ806, Pros, development, colitis (disease), CAC, Signs and Symptoms, ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase activity, 4.2.1.1, vps34, dp110, core, D-Akt, TFIID, beta[[3]] tubulin, PI3CG, PI-3-K, cac, PI3K-59F, akt1, PI3K-Dp110, dAkt1, DRAC-PK66, beta60C, class III, Glandular Epithelial Cells, Colon cancer, AA415488, l(3)86Ca, p110gamma, Drug, Meis1, Preparations, dakt1, DmelCG7128, Therapeutic, approaches, Innate Inflammatory Responses, malignant tumour of the colon, PKBalpha, Treatment, dAKT1, RAC, Rac, TAF8, growth, Pharmaceutical PreparationfalseColitis-associated colon cancerThis model looks at the development of colitis-associated colon cancer in order investigate the mechanism behind inflammation-associated tumorigenesis. Dynamic simulations reveal that P53, MDM2, and AKT may constitute a core network responsible for the malignant transformation of colon epithelial cells in a pro-tumor inflammatory environment. This model can aid in furthering mechanistic studies on colitis-associated colon cancer in addition to identifying novel cancer therapies. 2016-06-172017-01-302017-01-30460126446703