2024
Epigenetic heterogeneity hotspots in human liver disease progression
Hlady R, Zhao X, Khoury L, Wagner R, Luna A, Pham K, Pyrosopoulos N, Jain D, Wang L, Liu C, Robertson K. Epigenetic heterogeneity hotspots in human liver disease progression. Hepatology 2024, 81: 1197-1210. PMID: 39028883, PMCID: PMC11742070, DOI: 10.1097/hep.0000000000001023.Peer-Reviewed Original ResearchEpigenetic heterogeneityGenome-wide profiling of DNA methylationProfiling of DNA methylationDNA methylation landscapeGenome-wide profilingGene expression heterogeneityCopy number variationsMethylation landscapeOnset of liver cancerDNA methylationLiver disease developmentPhenotypic effectsNumber variationsGenetic heterogeneityTranscriptional heterogeneityFunctional screeningLiver disease progressionCopy numberExpression heterogeneityGene expressionTumor suppressorHuman diseasesGenesPathological phenotypesKey pathways
2023
EPCO-34. IMAGE-BASED PHENOTYPIC HIGH-CONTENT CRISPR-CAS9 SCREEN FOR CHARACTERIZING CANCER DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA
Amin S, Gujar A, Yi E, Kang W, Costa M, Gabriel P, Sjogren G, Maher L, Lee C, Robson P, Dickinson P, Packer R, Courtois E, Verhaak R. EPCO-34. IMAGE-BASED PHENOTYPIC HIGH-CONTENT CRISPR-CAS9 SCREEN FOR CHARACTERIZING CANCER DRIVERS IN PEDIATRIC HIGH-GRADE GLIOMA. Neuro-Oncology 2023, 25: v131-v131. PMCID: PMC10639707, DOI: 10.1093/neuonc/noad179.0497.Peer-Reviewed Original ResearchKnockout phenotypesWhole genome sequencing datasetsPediatric high-grade gliomasCancer Dependency MapCancer aneuploidyCell morphological featuresKnockout screensOntology analysisCancer driversSequencing datasetsHigh-content screening systemTumor suppressorFocal amplificationDriver genesGenomic landscapeHigh-grade glioma cell linesGenesLive cell imagesGlioma cell linesCell membraneDependency MapSingle cellsApoptotic cellsCell linesCRISPROncogenic context shapes the fitness landscape of tumor suppression
Blair L, Juan J, Sebastian L, Tran V, Nie W, Wall G, Gerceker M, Lai I, Apilado E, Grenot G, Amar D, Foggetti G, Do Carmo M, Ugur Z, Deng D, Chenchik A, Paz Zafra M, Dow L, Politi K, MacQuitty J, Petrov D, Winslow M, Rosen M, Winters I. Oncogenic context shapes the fitness landscape of tumor suppression. Nature Communications 2023, 14: 6422. PMID: 37828026, PMCID: PMC10570323, DOI: 10.1038/s41467-023-42156-y.Peer-Reviewed Original ResearchHuman nucleolar protein 7 (NOL7) is required for early pre-rRNA accumulation and pre-18S rRNA processing
McCool M, Bryant C, Huang H, Ogawa L, Farley-Barnes K, Sondalle S, Abriola L, Surovtseva Y, Baserga S. Human nucleolar protein 7 (NOL7) is required for early pre-rRNA accumulation and pre-18S rRNA processing. RNA Biology 2023, 20: 257-271. PMID: 37246770, PMCID: PMC10228412, DOI: 10.1080/15476286.2023.2217392.Peer-Reviewed Original ResearchConceptsPre-rRNA accumulationRibosome biogenesisNonessential roleEukaryotic ribosome biogenesisEssential cellular processesNucleolar stress responsePre-rRNA levelsRRNA processingLikely orthologCellular processesAssociated proteinsTumor suppressorStress responseHuman cellsProtein synthesisProtein 7Human counterpartBiogenesisYeastOrthologsHomologSubcomplexAccumulationRRNATranscriptionPTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6
Yu Y, Dai M, Huang L, Chen W, Yu E, Mendoza A, Michael H, Khanna C, Bosenberg M, McMahon M, Merlino G. PTEN phosphatase inhibits metastasis by negatively regulating the Entpd5/IGF1R pathway through ATF6. IScience 2023, 26: 106070. PMID: 36824269, PMCID: PMC9942123, DOI: 10.1016/j.isci.2023.106070.Peer-Reviewed Original ResearchProtein phosphatase activityPhosphatase activityPTEN protein phosphatase activityER stress sensor ATF6ER stressPTEN phosphatase activityPTEN expressionMelanoma cell invasivenessNovel candidate therapeutic targetInhibits metastasisIGF1R pathwayIGF1R levelsHuman melanoma samplesTumor suppressorCandidate therapeutic targetCell invasivenessATF6Melanoma samplesMetastatic progressionTherapeutic targetExpressionDose-dependent mannerPathwayMouse melanoma modelMutant melanoma
2022
ACTR5 controls CDKN2A and tumor progression in an INO80-independent manner
Xu X, Chan A, Li M, Liu Q, Mattson N, Pokharel S, Chang W, Yuan Y, Wang J, Moore R, Pirrotte P, Wu J, Su R, Müschen M, Rosen S, Chen J, Yang L, Chen C. ACTR5 controls CDKN2A and tumor progression in an INO80-independent manner. Science Advances 2022, 8: eadc8911. PMID: 36563143, PMCID: PMC9788768, DOI: 10.1126/sciadv.adc8911.Peer-Reviewed Original ResearchCell cycle signalingCRISPR interference screenCell cycle machineryHallmark of tumorigenesisINO80 chromatinInterference screenEpigenetic regulatorsTumor progressionEpigenetic mechanismsCycle machineryEpigenetic dysregulationComplex membersTumor suppressorCell cycleCRISPR geneHCC tumor growthIes6CDKN2A expressionPharmacological inhibitionSignalingMultiple cancersHCC proliferationNovel opportunitiesTumor growthDynamic interplayDouble knockout CRISPR screen for cancer resistance to T cell cytotoxicity
Park J, Codina A, Ye L, Lam S, Guo J, Clark P, Zhou X, Peng L, Chen S. Double knockout CRISPR screen for cancer resistance to T cell cytotoxicity. Journal Of Hematology & Oncology 2022, 15: 172. PMID: 36456981, PMCID: PMC9716677, DOI: 10.1186/s13045-022-01389-y.Peer-Reviewed Original ResearchConceptsT cell cytotoxicityCell cytotoxicityT cell killingTumor suppressorCancer patientsImmune responseAvailable agentsSurvival analysisClinical patientsCancer treatmentCancer cellsCancer resistanceDirect targetingPotential new conceptCancer mutationsPatientsCell killingNormal samplesResistance pathwaysCellular responsesSuch resistanceCytotoxicityResistance genesSH3 domain regulation of RhoGAP activity: Crosstalk between p120RasGAP and DLC1 RhoGAP
Chau JE, Vish KJ, Boggon TJ, Stiegler AL. SH3 domain regulation of RhoGAP activity: Crosstalk between p120RasGAP and DLC1 RhoGAP. Nature Communications 2022, 13: 4788. PMID: 35970859, PMCID: PMC9378701, DOI: 10.1038/s41467-022-32541-4.Peer-Reviewed Original ResearchConceptsRhoGAP activitySH3 domainCatalytic arginine fingerIntrinsic GTPase activityRho family GTPasesLiver cancer 1GAP proteinsRhoGAP proteinArginine fingerCo-crystal structureRas GTPasesGAP activityRho proteinsCellular processesGTPase activityMolecular basisKey regulatorTumor suppressorP120RasGAPCell migrationProteinGTPasesRhoGAPCancer 1Binding sitesExtensive protein dosage compensation in aneuploid human cancers
Schukken KM, Sheltzer J. Extensive protein dosage compensation in aneuploid human cancers. Genome Research 2022, 32: 1254-1270. PMID: 35701073, PMCID: PMC9341510, DOI: 10.1101/gr.276378.121.Peer-Reviewed Original ResearchConceptsDosage compensationPost-translational regulatory mechanismsProtein complex subunitsCopy numberHuman cancersCell cycle genesEffects of aneuploidyMajority of proteinsChromosome copy numberProtein expression dataKey driver genesChromosome copy number changesExpression of oncogenesCopy number changesKey cancer driversComplex subunitsCycle genesGene groupsCancer driversCancer proteomeRegulatory mechanismsTumor suppressorExpression dataDriver genesChromosome gainsBiallelic inactivation of PBRM1 as a molecular driver in a rare pineoblastoma case: illustrative case
Antonios JP, Yalcin K, Darbinyan A, Koo A, Hong CS, DiLuna M, Erson-Omay Z. Biallelic inactivation of PBRM1 as a molecular driver in a rare pineoblastoma case: illustrative case. Journal Of Neurosurgery Case Lessons 2022, 3: case2213. PMID: 36303510, PMCID: PMC9379698, DOI: 10.3171/case2213.Peer-Reviewed Original ResearchMolecular driversPineal parenchymal tumorsRenal cell carcinomaRare tumor typeParenchymal tumorsCell carcinomaBladder carcinomaPapillary featuresPineoblastomaTumor subtypesTumor typesConsensus groupBiallelic lossGenomic profilingCancer typesMolecular level alterationsLevel alterationsGenomic driversBiallelic inactivationCarcinomaDriver eventsTumor suppressorGenetic phenotypesPathway changesMultiomics studiesIntegrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis
Farshidfar F, Rhrissorrakrai K, Levovitz C, Peng C, Knight J, Bacchiocchi A, Su J, Yin M, Sznol M, Ariyan S, Clune J, Olino K, Parida L, Nikolaus J, Zhang M, Zhao S, Wang Y, Huang G, Wan M, Li X, Cao J, Yan Q, Chen X, Newman AM, Halaban R. Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis. Nature Communications 2022, 13: 898. PMID: 35197475, PMCID: PMC8866401, DOI: 10.1038/s41467-022-28566-4.Peer-Reviewed Original ResearchConceptsAcral melanomaMelanoma subtypesClinical profilingCommon melanoma subtypeImmune checkpoint blockadeCheckpoint blockadeInferior survivalMelanoma cell linesKey molecular driversPoor prognosisTherapeutic targetAnchorage-independent growthImmunomodulatory genesNon-white individualsHotspot mutationsMolecular driversCandidate oncogeneMelanomaApoptotic cell deathLZTR1Focal amplificationTumor promoterCell linesMetastasisTumor suppressorProteogenomic and clinical implications of unique recurrent splice variants in clear cell renal cell carcinoma.
Chang A, Stewart P, Chakiryan N, Soupir A, Tian Y, Du D, Teer J, Kim Y, Spiess P, Chahoud J, Zhang Y, Koomen J, Berglund A, Wang L, Robinson T, Manley B. Proteogenomic and clinical implications of unique recurrent splice variants in clear cell renal cell carcinoma. Journal Of Clinical Oncology 2022, 40: 380-380. DOI: 10.1200/jco.2022.40.6_suppl.380.Peer-Reviewed Original ResearchGenotype-Tissue Expression (GTEx) projectRNA-seq dataClear cell renal cell carcinomaSplice variantsClinical Proteomic Tumor Analysis ConsortiumBulk RNA-seq dataCell renal cell carcinomaAlternative mRNA splicingAberrant splice variantsCancer Cell Line EncyclopediaProteomic diversityProteogenomic analysisCancer Genome AtlasMRNA splicingExpression projectPathway enrichmentSplicing processTumor suppressorNew pathogenic mechanismGenomic mutationsNovel pipelineAnalysis ConsortiumOncogenic pathwaysCancer-specific survivalGenome AtlasCircular RNA ANAPC7 Inhibits Tumor Growth and Muscle Wasting via PHLPP2–AKT–TGF-β Signaling Axis in Pancreatic Cancer
Shi X, Yang J, Liu M, Zhang Y, Zhou Z, Luo W, Fung K, Xu C, Bronze M, Houchen C, Li M. Circular RNA ANAPC7 Inhibits Tumor Growth and Muscle Wasting via PHLPP2–AKT–TGF-β Signaling Axis in Pancreatic Cancer. Gastroenterology 2022, 162: 2004-2017.e2. PMID: 35176309, PMCID: PMC10428768, DOI: 10.1053/j.gastro.2022.02.017.Peer-Reviewed Original ResearchConceptsZinc-dependent transcription factorsFunction of circRNAsMiR-373Dephosphorylation of AktDephosphorylation of CREBNovel tumor suppressorCyclin D1Feed-forward loopMouse skeletal muscleHuman pancreatic cancer cellsRNA interactionsTumor growthTranscription factorsCircular RNAsPancreatic cancer progressionMuscle wastingAkt dephosphorylationRNA immunoprecipitationCancer cell proliferationDownstream targetsPancreatic cancer cellsTumor suppressorSilico analysisPancreatic cancerSignaling Axis
2021
Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity
Park J, Daniels J, Wartewig T, Ringbloom KG, Martinez-Escala ME, Choi S, Thomas JJ, Doukas PG, Yang J, Snowden C, Law C, Lee Y, Lee K, Zhang Y, Conran C, Tegtmeyer K, Mo SH, Pease DR, Jothishankar B, Kwok PY, Abdulla FR, Pro B, Louissaint A, Boggon T, Sosman J, Guitart J, Rao D, Ruland J, Choi J. Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity. Blood 2021, 138: 1225-1236. PMID: 34115827, PMCID: PMC8499046, DOI: 10.1182/blood.2020009655.Peer-Reviewed Original ResearchConceptsPutative driver genesDriver genesCutaneous T-cell lymphomaDisease phenotypePutative tumor suppressorT-cell lymphomaMycosis fungoidesDiverse disease phenotypesPutative genetic causesSezary syndromeDNA/RNA sequencingGenomic analysisRNA sequencingMolecular basisTumor suppressorDisease stageStructural variantsGenetic relationshipsTranscriptional signatureGenesDisease heterogeneityFunctional assaysNovel insightsSkin-homing T cellsLeukemic diseaseThe cell adhesion molecule TMIGD1 binds to moesin and regulates tubulin acetylation and cell migration
Rahimi N, Ho R, Chandler K, De La Cena K, Amraei R, Mitchel A, Engblom N, Costello C. The cell adhesion molecule TMIGD1 binds to moesin and regulates tubulin acetylation and cell migration. Journal Of Biomedical Science 2021, 28: 61. PMID: 34503512, PMCID: PMC8427838, DOI: 10.1186/s12929-021-00757-z.Peer-Reviewed Original ResearchConceptsMitotic spindle organizationERM familyΑ-tubulinSpindle organizationCell migrationApical localizationN-terminal ERM domainCRISPR/Cas9-mediated knockoutMitotic spindle assemblyCell-cell adhesionCas9-mediated knockoutFilopodia-like protrusionsNovel tumor suppressorComplex functional interplayActin organizationERM domainLysine acetylationTMIGD1Spindle assemblyCarboxyl terminusFunctional interplayMoesinCell cycleTumor suppressorEzrinIntegrated mutational landscape analysis of uterine leiomyosarcomas
Choi J, Manzano A, Dong W, Bellone S, Bonazzoli E, Zammataro L, Yao X, Deshpande A, Zaidi S, Guglielmi A, Gnutti B, Nagarkatti N, Tymon-Rosario JR, Harold J, Mauricio D, Zeybek B, Menderes G, Altwerger G, Jeong K, Zhao S, Buza N, Hui P, Ravaggi A, Bignotti E, Romani C, Todeschini P, Zanotti L, Odicino F, Pecorelli S, Ardighieri L, Bilguvar K, Quick CM, Silasi DA, Huang GS, Andikyan V, Clark M, Ratner E, Azodi M, Imielinski M, Schwartz PE, Alexandrov LB, Lifton RP, Schlessinger J, Santin AD. Integrated mutational landscape analysis of uterine leiomyosarcomas. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2025182118. PMID: 33876771, PMCID: PMC8053980, DOI: 10.1073/pnas.2025182118.Peer-Reviewed Original ResearchConceptsHomologous recombination DNA repair deficiencySequencing dataWhole-genome sequencing dataRNA sequencing dataTCGA samplesCopy number variation analysisATRX/DAXXCopy number lossNumber variation analysisDNA repair deficiencyWhole-exome sequencing dataRecurrent somatic mutationsCopy number gainsCancer Genome AtlasPatient-derived xenograftsTumor suppressorAkt geneGenetic landscapeHRD signaturesPTEN geneGenesMost fusionsC-MycMutational signaturesC-myc/AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer
Beck AC, Cho E, White JR, Paemka L, Li T, Gu VW, Thompson DT, Koch KE, Franke C, Gosse M, Wu VT, Landers SR, Pamatmat AJ, Kulak MV, Weigel RJ. AP-2α Regulates S-Phase and Is a Marker for Sensitivity to PI3K Inhibitor Buparlisib in Colon Cancer. Molecular Cancer Research 2021, 19: 1156-1167. PMID: 33753551, PMCID: PMC8254761, DOI: 10.1158/1541-7786.mcr-20-0867.Peer-Reviewed Original ResearchMeSH KeywordsAminopyridinesAnimalsBiomarkers, TumorCell Line, TumorCell SurvivalColonic NeoplasmsGene Expression ProfilingGene Expression Regulation, NeoplasticGene Knockout TechniquesHCT116 CellsHumansMiceMorpholinesPhosphoinositide-3 Kinase InhibitorsRNA InterferenceRNA-SeqS PhaseTranscription Factor AP-2Xenograft Model Antitumor AssaysConceptsAP-2αPI3K inhibitorsColon cancer cell linesCell cycleS phasePrimary gene targetsK inhibitorsChromatin immunoprecipitation sequencingCancer cell linesPI3K cascadeProlonged S phaseCell linesActivation of AktShort hairpin RNAPhosphorylation of AktHistone H3Immunoprecipitation sequencingRNA sequencingPI3K inhibitionTarget genesK cascadeGene targetsTumor suppressorHairpin RNAColon cancerAltered endocytosis in cellular senescence
Shin EY, Soung NK, Schwartz MA, Kim EG. Altered endocytosis in cellular senescence. Ageing Research Reviews 2021, 68: 101332. PMID: 33753287, PMCID: PMC8131247, DOI: 10.1016/j.arr.2021.101332.Peer-Reviewed Original ResearchGenetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In VivoTumor Suppressor Genes and EGFR-Driven Lung Adenocarcinoma
Foggetti G, Li C, Cai H, Hellyer JA, Lin WY, Ayeni D, Hastings K, Choi J, Wurtz A, Andrejka L, Maghini DG, Rashleigh N, Levy S, Homer R, Gettinger SN, Diehn M, Wakelee HA, Petrov DA, Winslow MM, Politi K. Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In VivoTumor Suppressor Genes and EGFR-Driven Lung Adenocarcinoma. Cancer Discovery 2021, 11: 1736-1753. PMID: 33707235, PMCID: PMC8530463, DOI: 10.1158/2159-8290.cd-20-1385.Peer-Reviewed Original ResearchConceptsSuppressor geneKey tumor suppressorPutative tumor suppressor geneTumor suppressor geneSensitivity of EGFRTumor growthOncogenic contextTumor suppressorHuman EGFRGenetic determinantsKeap1 pathwayComplex genotypesTumor suppressor gene alterationsLung cancer growthGenesDeficient lung adenocarcinomaLung adenocarcinomaGenetic alterationsIssue featureStrong driverCancer growthEGFR inhibitorsKinase inhibitorsInactivationGene alterations
2020
Flow Cytometric Analyses of p53-Mediated Cell Cycle Arrest and Apoptosis in Cancer Cells
Al Zouabi NN, Roberts CM, Lin ZP, Ratner ES. Flow Cytometric Analyses of p53-Mediated Cell Cycle Arrest and Apoptosis in Cancer Cells. Methods In Molecular Biology 2020, 2255: 43-53. PMID: 34033093, DOI: 10.1007/978-1-0716-1162-3_5.Peer-Reviewed Original ResearchConceptsGene of interestCell cycle arrestCycle arrestCell typesDNA damaging agentsP53-mediated cell cycle arrestCell cycle progressionTumor suppressor p53Cellular contextEctopic expressionExogenous stressCell cycle distributionDamaging agentsCycle progressionTumor suppressorSuppressor p53Stable expressionPhenotypic analysisCell survivalCell deathGenomic damageP53 functionGenesEnvironmental insultsCycle distribution
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