Boris Kholodenko
Research
Publications
Featured Publications
Control of cell state transitions
Rukhlenko O, Halasz M, Rauch N, Zhernovkov V, Prince T, Wynne K, Maher S, Kashdan E, MacLeod K, Carragher N, Kolch W, Kholodenko B. Control of cell state transitions. Nature 2022, 609: 975-985. PMID: 36104561, PMCID: PMC9644236, DOI: 10.1038/s41586-022-05194-y.Peer-Reviewed Original ResearchConceptsCell state transitionsCell fateCell statesCell fate transitionsCell fate decisionsSingle-cell dataNew biological insightsFate transitionsMovement of cellsFate decisionsWaddington landscapePhenotypic dataBiological insightsOmics datasetsOmics dataCellular modelMechanistic modelLandscape1FateCellsDevelopment pathwaysLandscapeBiologyState transitionsTherapeutic interventionsA systematic analysis of signaling reactivation and drug resistance
Kholodenko B, Rauch N, Kolch W, Rukhlenko O. A systematic analysis of signaling reactivation and drug resistance. Cell Reports 2021, 35: 109157. PMID: 34038718, PMCID: PMC8202068, DOI: 10.1016/j.celrep.2021.109157.Peer-Reviewed Original ResearchPeriodic propagating waves coordinate RhoGTPase network dynamics at the leading and trailing edges during cell migration
Bolado-Carrancio A, Rukhlenko O, Nikonova E, Tsyganov M, Wheeler A, Garcia-Munoz A, Kolch W, von Kriegsheim A, Kholodenko B. Periodic propagating waves coordinate RhoGTPase network dynamics at the leading and trailing edges during cell migration. ELife 2020, 9: e58165. PMID: 32705984, PMCID: PMC7380942, DOI: 10.7554/elife.58165.Peer-Reviewed Original ResearchScaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops*
Kiyatkin A, Aksamitiene E, Markevich NI, Borisov NM, Hoek JB, Kholodenko BN. Scaffolding Protein Grb2-associated Binder 1 Sustains Epidermal Growth Factor-induced Mitogenic and Survival Signaling by Multiple Positive Feedback Loops*. Journal Of Biological Chemistry 2006, 281: 19925-19938. PMID: 16687399, PMCID: PMC2312093, DOI: 10.1074/jbc.m600482200.Peer-Reviewed Original ResearchConceptsEpidermal growth factorRas/MAPK signalingGab1 tyrosine phosphorylationGrowth factorRole of Gab1PI3K/Akt activationMultiple positive feedback loopsProtein Grb2Mutant proteinsScaffold proteinTyrosine phosphorylationBinder 1Positive feedback loopMitogenic pathwaysMAPK signalingEssential functionsSurvival signalingDiverse perturbationsCellular responsesAkt activationCytokine receptorsPharmacological inhibitorsGab1EGF dosesGrb2Untangling the wires: A strategy to trace functional interactions in signaling and gene networks
Kholodenko BN, Kiyatkin A, Bruggeman FJ, Sontag E, Westerhoff HV, Hoek JB. Untangling the wires: A strategy to trace functional interactions in signaling and gene networks. Proceedings Of The National Academy Of Sciences Of The United States Of America 2002, 99: 12841-12846. PMID: 12242336, PMCID: PMC130547, DOI: 10.1073/pnas.192442699.Peer-Reviewed Original ResearchConceptsGene networksFunctional interactionMitogen-activated protein kinase cascadeProtein kinase cascadeProteomic data setsKinase cascadeCellular signalingLarge genomicsUnidentified elementsMechanistic levelCellular networkingSignalingCell systemGenomicsInteractionInteraction routesCascadeComputer-generated responsesNetwork responseCurrent methodologiesResponse
2025
cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling
Deng H, Rukhlenko O, Joshi D, Hu X, Junk P, Tuliakova A, Kholodenko B, Schwartz M. cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling. Science Advances 2025, 11: eado9970. PMID: 39752487, PMCID: PMC11698091, DOI: 10.1126/sciadv.ado9970.Peer-Reviewed Original ResearchConceptsShear stressCell cycle-dependent kinasesHigh shear stressLow shear stressOscillatory shear stressPhysiological shear stressFluid shear stressCell cycle arrestRegulatory networksTranscriptomic statesResponse to drug treatmentCycle arrestCell cycleEndothelial cell cycleDisease susceptibilityRegulatory mechanismsVessel behaviorCDK2Endothelial cellsIn vitroStressRegulationVascular endothelial cellsRemodelingCells
2024
Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia
Jones L, Rukhlenko O, Dias T, Carmody C, Wynne K, Kholodenko B, Bond J. Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia. Blood 2024, 144: 4161-4161. DOI: 10.1182/blood-2024-207308.Peer-Reviewed Original ResearchAcute myeloid leukemiaPatient-derived xenograftsCombination-treated miceInhibitor combinationsPeripheral bloodPhosphorylated ERKBone marrowRAS pathway activationSpleen weightMyeloid leukemiaAML patient-derived xenograftDrug combinationsVehicle controlSingle agentHuman CD45+ cellsPre-clinical mouse modelPediatric acute myeloid leukemiaAssociated with poor outcomesHigh-risk patient groupsMedian spleen weightSB-treated micePreclinical in vivo modelsCD45+ cellsLateral tail veinPathway activationEV017/#1282 GLP-1 analogues reduce the incidence of endometrial cancer in an animal model
Wilkinson M, Mulligan K, Moran B, Rukhlenko O, Kashdan E, Kholodenko B, Fabre A, Mccormack J, Docherty N, Le Roux C, Brennan D. EV017/#1282 GLP-1 analogues reduce the incidence of endometrial cancer in an animal model. International Journal Of Gynecological Cancer 2024, 34: a92. DOI: 10.1136/ijgc-2024-igcs.136.Peer-Reviewed Original ResearchCell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells
Sevrin T, Imoto H, Robertson S, Rauch N, Dyn'ko U, Koubova K, Wynne K, Kolch W, Rukhlenko O, Kholodenko B. Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells. Cell Reports 2024, 43: 114710. PMID: 39240715, PMCID: PMC11474227, DOI: 10.1016/j.celrep.2024.114710.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaResistance to RAFResistant PDAC cellsPancreatic cancer cellsPancreatic ductal adenocarcinoma cell linesProtein expression profilesTumor-specific variationsIsogenic pairsCell-specific modelsConformational specificityERK signalingInhibitor combinationsERK pathwayKRAS mutationsTargeted therapyExpression profilesMEK inhibitorsDuctal adenocarcinomaCancer cellsKRAS mutantPhospho-ERKCell linesPDAC cellsCell viabilityDifferential sensitivityCell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets
Rukhlenko O, Imoto H, Tambde A, McGillycuddy A, Junk P, Tuliakova A, Kolch W, Kholodenko B. Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets. Cancers 2024, 16: 2354. PMID: 39001416, PMCID: PMC11240448, DOI: 10.3390/cancers16132354.Peer-Reviewed Original ResearchControl of cell movementCell linesCell statesLuminal BC cellsControl cell phenotypeWaddington landscapeTissue-derived cell linesCell movementOncogenic transformationSmall molecule inhibitorsSignaling nodeBC cell linesExpression profilesPerturbation datasetsNormal cell stateMolecule inhibitorsBC cellsCell phenotypeBasal BCBC subtypesBreast cancerOncogenic driversCellsCurrent biologicsBreast tissue cells