2024
Immune infiltration at the primary tumor is associated with clinical outcome of patients with extranodal extension of lymph node metastasis in oral cancer
Michikawa C, Gleber-Netto F, Pickering C, Rao X, Wang J, Sikora A, Myers J, Frederick M. Immune infiltration at the primary tumor is associated with clinical outcome of patients with extranodal extension of lymph node metastasis in oral cancer. Oral Oncology 2024, 153: 106729. PMID: 38663156, DOI: 10.1016/j.oraloncology.2024.106729.Peer-Reviewed Original ResearchConceptsOral cavity squamous cell carcinomaAssociated with clinical outcomesExtranodal extensionLymph node metastasisImmune infiltrationImmune infiltration statusOverall survivalPrimary tumorNode metastasisOral cancerInfiltration statusClinical outcomes of OSCC patientsExtension of lymph node metastasesAssociated with clinical outcomes of patientsAssociated with OS rateLocally advanced oral cancerClinical outcomes of patientsOutcome of OSCC patientsAssociated with poor overall survivalImmune infiltration of tumorsLow immune infiltrationNode negative tumorsAdvanced oral cancerHuman papillomavirus-negativeInfiltration of tumorsHistologic and Genomic Analysis of Conjunctival SCC in African and American Cohorts Reveal UV Light and HPV Signatures and High Tumor Mutation Burden
Gleber-Netto F, Nagarajan P, Sagiv O, Pickering C, Gross N, Ning J, Yeshi M, Mitku Y, Tetzlaff M, Esmaeli B. Histologic and Genomic Analysis of Conjunctival SCC in African and American Cohorts Reveal UV Light and HPV Signatures and High Tumor Mutation Burden. Investigative Ophthalmology & Visual Science 2024, 65: 24. PMID: 38597722, PMCID: PMC11008748, DOI: 10.1167/iovs.65.4.24.Peer-Reviewed Original ResearchConceptsHigh-risk human papillomavirusTumor mutational burdenMutational burdenHistological featuresHigh risk human papillomavirus statusConjunctival squamous cell carcinomaHigh tumor mutational burdenDensity of CD8+PD-L1 expressionTumor-infiltrating lymphocytesCD3+ cellsTumors of patientsSquamous cell carcinomaWhole-exome sequencingPotential treatment strategySCC subtypeThicker tumorsPD-L1CD8+Cell carcinomaHuman papillomavirusCutaneous SCCGenomic alterationsCancer Genome AtlasTreatment strategiesMutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response
Zhao M, Wang T, Gleber-Netto F, Chen Z, McGrail D, Gomez J, Ju W, Gadhikar M, Ma W, Shen L, Wang Q, Tang X, Pathak S, Raso M, Burks J, Lin S, Wang J, Multani A, Pickering C, Chen J, Myers J, Zhou G. Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response. Nature Communications 2024, 15: 180. PMID: 38167338, PMCID: PMC10761733, DOI: 10.1038/s41467-023-44239-2.Peer-Reviewed Original Research
2023
Deep learning of cell spatial organizations identifies clinically relevant insights in tissue images
Wang S, Rong R, Zhou Q, Yang D, Zhang X, Zhan X, Bishop J, Chi Z, Wilhelm C, Zhang S, Pickering C, Kris M, Minna J, Xie Y, Xiao G. Deep learning of cell spatial organizations identifies clinically relevant insights in tissue images. Nature Communications 2023, 14: 7872. PMID: 38081823, PMCID: PMC10713592, DOI: 10.1038/s41467-023-43172-8.Peer-Reviewed Original ResearchFAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner.
Pifer P, Yang L, Kumar M, Xie T, Frederick M, Hefner A, Beadle B, Molkentine D, Molkentine J, Dhawan A, Abdelhakiem M, Osman A, Leibowitz B, Myers J, Pickering C, Sandulache V, Heymach J, Skinner H. FAK drives resistance to therapy in HPV-negative head and neck cancer in a p53-dependent manner. Clinical Cancer Research 2023, 30: 187-197. PMID: 37819945, PMCID: PMC10767302, DOI: 10.1158/1078-0432.ccr-23-0964.Peer-Reviewed Original ResearchConceptsHPV-negative headHPV-negative HNSCC tumorsWorse disease-free survivalNeck squamous cell carcinomaMutant TP53HPV-negative HNSCC cell linesBackbone of therapyDisease-free survivalPlatinum-based chemotherapySquamous cell carcinomaHPV-negative HNSCCHNSCC cell linesCell linesWild-type TP53Cisplatin-resistant cell linesCell carcinomaHNSCC cohortNeck cancerHNSCC tumorsVivo shRNA screenWorse outcomesDeep learning‐based pathology image analysis predicts cancer progression risk in patients with oral leukoplakia
Zhang X, Gleber‐Netto F, Wang S, Martins‐Chaves R, Gomez R, Vigneswaran N, Sarkar A, William W, Papadimitrakopoulou V, Williams M, Bell D, Palsgrove D, Bishop J, Heymach J, Gillenwater A, Myers J, Ferrarotto R, Lippman S, Pickering C, Xiao G. Deep learning‐based pathology image analysis predicts cancer progression risk in patients with oral leukoplakia. Cancer Medicine 2023, 12: 7508-7518. PMID: 36721313, PMCID: PMC10067069, DOI: 10.1002/cam4.5478.Peer-Reviewed Original ResearchConceptsLow-risk groupOral leukoplakiaOL patientsProgression riskOral mucosaHigh-risk patientsOral cancer developmentRisk stratification modelCancer progression riskLarge interobserver variabilityEarly diagnosisHigh riskDysplasia gradingAbnormal morphological featuresOral epitheliumOC developmentEarly interventionLow-risk onesPatientsStratification modelCancer developmentCancer progressionInterobserver variabilityLeukoplakiaRiskHRAS Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma
Coleman N, Marcelo K, Hopkins J, Khan N, Du R, Hong L, Park E, Balsara B, Leoni M, Pickering C, Myers J, Heymach J, Albacker L, Hong D, Gillison M, Le X. HRAS Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma. JCO Precision Oncology 2023, 7: e2200211. PMID: 36603172, PMCID: PMC9928766, DOI: 10.1200/po.22.00211.Peer-Reviewed Original ResearchConceptsNeck squamous cell carcinomaMD Anderson Cancer CenterSquamous cell carcinomaAnderson Cancer CenterCo-occurring mutationsClinical courseSurvival outcomesCancer CenterCell carcinomaShorter disease-free survivalPoor clinic outcomePrimary definitive treatmentTherapeutic combination strategiesDisease-free survivalPoor clinical outcomePatient demographic informationImproved OSDefinitive treatmentMedian ageOverall survivalFoundation MedicineMale patientsClinical outcomesClinic outcomesTreatment response
2022
Mildly dysplastic oral lesions with optically-detectable abnormalities share genetic similarities with severely dysplastic lesions
Brenes D, Nipper A, Tan M, Gleber-Netto F, Schwarz R, Pickering C, Williams M, Vigneswaran N, Gillenwater A, Sikora A, Richards-Kortum R. Mildly dysplastic oral lesions with optically-detectable abnormalities share genetic similarities with severely dysplastic lesions. Oral Oncology 2022, 135: 106232. PMID: 36335817, PMCID: PMC9881670, DOI: 10.1016/j.oraloncology.2022.106232.Peer-Reviewed Original ResearchConceptsOral premalignant lesionsMild dysplasiaSevere dysplasiaOral lesionsPremalignant lesionsDysplastic oral lesionsHigh-grade pathologySubset of lesionsLoss of autofluorescenceDysplastic lesionsOptical imaging studiesOral surgeryDysplasiaDetectable abnormalitiesPatient careLesionsImaging studiesEpithelial cell nucleiPatientsGene expressionGene expression profilesMarkersGene expression analysisSimilar gene expressionExpression profilesClinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma
Rodriguez CP, Kang H, Geiger JL, Burtness B, Chung CH, Pickering CR, Fakhry C, Le QT, Yom SS, Galloway TJ, Golemis E, Li A, Shoop J, Wong S, Mehra R, Skinner H, Saba NF, Flores ER, Myers JN, Ford JM, Karchin R, Ferris RL, Kunos C, Lynn JM, Malik S. Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma. Journal Of The National Cancer Institute 2022, 114: 1619-1627. PMID: 36053203, PMCID: PMC9745425, DOI: 10.1093/jnci/djac163.Peer-Reviewed Original ResearchConceptsNeck squamous cell carcinomaSquamous cell carcinomaClinical trialsCell carcinomaTrial designTP53 mutationsNational Clinical Trials NetworkMetastatic disease settingsClinical trial developmentClinical Trials NetworkNovel therapeutic approachesNational Cancer InstituteMetastatic headTP53-mutated tumorsWorse outcomesClinical studiesFrequent genetic eventTherapeutic approachesCancer InstituteTrial developmentBreakout groupsPatientsDisease settingsBiomarker integrationTrials NetworkCombined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers.
Ghosh S, Mazumdar T, Xu W, Powell RT, Stephan C, Shen L, Shah PA, Pickering CR, Myers JN, Wang J, Frederick MJ, Johnson FM. Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers. Clinical Cancer Research 2022, 28: 4479-4493. PMID: 35972731, PMCID: PMC9588713, DOI: 10.1158/1078-0432.ccr-22-1627.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphatasesAlphapapillomavirusApoptosisATPases Associated with Diverse Cellular ActivitiesAurora KinasesCell Cycle ProteinsFemaleHumansOncogene Proteins, ViralPapillomaviridaePapillomavirus E7 ProteinsPapillomavirus InfectionsRetinoblastoma ProteinUterine Cervical NeoplasmsConceptsHPV-positive cancer cellsInhibition-induced apoptosisAurora kinase inhibitorsAurora kinase inhibitionCancer cellsKinase inhibitionAbsence of RbViral oncoprotein E7Kinase inhibitorsMitotic exitAAA-ATPaseProtein degradationRb functionMechanisms of sensitivityPathway componentsTRIP13MAD2L1Extensive apoptosisCancer cell linesSquamous cancer cell linesApoptosisCell linesRetinoblastoma expressionBUB1BProtein expression correlatesMutant p53 drives an immune cold tumor immune microenvironment in oral squamous cell carcinoma
Shi Y, Xie T, Wang B, Wang R, Cai Y, Yuan B, Gleber-Netto FO, Tian X, Rodriguez-Rosario AE, Osman AA, Wang J, Pickering CR, Ren X, Sikora AG, Myers JN, Rangel R. Mutant p53 drives an immune cold tumor immune microenvironment in oral squamous cell carcinoma. Communications Biology 2022, 5: 757. PMID: 35902768, PMCID: PMC9334280, DOI: 10.1038/s42003-022-03675-4.Peer-Reviewed Original ResearchConceptsOral cavity squamous cell carcinomaTumor immune microenvironmentCold tumor immune microenvironmentSquamous cell carcinomaICI therapyOSCC modelCell carcinomaImmune microenvironmentCold tumorsCell death protein 1 (PD-1) inhibitorsCancer cell-intrinsic mechanismsImmune checkpoint inhibitor therapyOral squamous cell carcinomaCheckpoint inhibitor therapyCombination ICI treatmentEffective immunotherapeutic approachesInterferon genes (STING) agonistImmunosuppressive M2 macrophagesProtein 1 inhibitorTobacco-associated cancersICI responsivenessICI treatmentCell-intrinsic mechanismsImmunotherapeutic approachesInhibitor therapyFusobacterium is enriched in oral cancer and promotes induction of programmed death-ligand 1 (PD-L1)
Michikawa C, Gopalakrishnan V, Harrandah AM, Karpinets TV, Garg RR, Chu RA, Park YP, Chukkapallia SS, Yadlapalli N, Erikson-Carter KC, Gleber-Netto FO, Sayour E, Progulske-Fox A, Chan , Wu X, Zhang J, Jobin C, Wargo JA, Pickering CR, Myers JN, Silver N. Fusobacterium is enriched in oral cancer and promotes induction of programmed death-ligand 1 (PD-L1). Neoplasia 2022, 31: 100813. PMID: 35834946, PMCID: PMC9287628, DOI: 10.1016/j.neo.2022.100813.Peer-Reviewed Original ResearchConceptsPD-L1 expressionAdjacent normal tissuesWhole-exome sequencingNormal tissuesNeck cancerOral tongue squamous cell carcinoma patientsTongue squamous cell carcinoma patientsSquamous cell carcinoma patientsTumor samplesPD-L1 mRNA expressionPD-L1 protein expressionOral tongue SCCCell carcinoma patientsOral tongue cancerImmune cell infiltrationPD-L1 mRNATumor immune microenvironmentNeck SCC cell linesNeck cancer cell linesSCC cell linesDevelopment of headCell linesCancer cell linesTongue SCCCarcinoma patientsA general calculus of fitness landscapes finds genes under selection in cancers
Hsu TK, Asmussen J, Koire A, Choi BK, Gadhikar M, Huh E, Lin CH, Konecki D, Kim YW, Pickering C, Kimmel M, Donehower L, Frederick M, Myers JN, Katsonis P, Lichtarge O. A general calculus of fitness landscapes finds genes under selection in cancers. Genome Research 2022, 32: gr.275811.121. PMID: 35301263, PMCID: PMC9104707, DOI: 10.1101/gr.275811.121.Peer-Reviewed Original ResearchConceptsEvolution of traitsFitness landscapeGenotype-phenotype relationshipsEvolutionary relationshipsComplex traitsPositive selectionGenomic searchSpecific traitsCancer InsightsGenesGenetic variantsFunctional impactTraitsExperimental supportLandscapeVariantsPhenotypeEvolutionSelectionGenotypesCancer cohortp16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade
Molkentine DP, Molkentine JM, Bridges KA, Valdecanas DR, Dhawan A, Bahri R, Hefner AJ, Kumar M, Yang L, Abdelhakiem M, Pifer PM, Sandulache V, Sheth A, Beadle BM, Thames HD, Mason KA, Pickering CR, Meyn RE, Skinner HD. p16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade. Cancer Research 2022, 82: 916-928. PMID: 34965932, PMCID: PMC9136619, DOI: 10.1158/0008-5472.can-21-2101.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Squamous CellCarrier ProteinsCyclin-Dependent Kinase Inhibitor p16DNA DamageDNA, ViralHead and Neck NeoplasmsHumansPapillomaviridaePapillomavirus InfectionsSignal TransductionSquamous Cell Carcinoma of Head and NeckTumor Suppressor ProteinsUbiquitinUbiquitin-Protein LigasesUbiquitin-Specific Peptidase 7ConceptsUbiquitin-specific protease 7DNA damage repairDamage repairHPV-positive tumorsTranscription factor Sp1Human papillomavirusFactor Sp1Neck squamous cell carcinoma cellsDNA-damaging therapiesRenders cellsHomologous recombinationSignaling cascadesHPV-negative diseaseSquamous cell carcinoma cellsHPV-negative counterpartsHPV-positive diseaseSquamous cell carcinomaUSP7 inhibitorsDNA damageHPV-negative HNSCCFunctional roleDegradation pathwayHPV positivityPathwayUndiscovered pathwaysGenetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy
Rangel R, Pickering CR, Sikora AG, Spiotto MT. Genetic Changes Driving Immunosuppressive Microenvironments in Oral Premalignancy. Frontiers In Immunology 2022, 13: 840923. PMID: 35154165, PMCID: PMC8829003, DOI: 10.3389/fimmu.2022.840923.Peer-Reviewed Original ResearchConceptsOral premalignant lesionsImmunosuppressive microenvironmentProgression of OPLsOral cavity cancerGenomic alterationsImmune microenvironmentOral cancerOSCC progressionInflammatory environmentPremalignant lesionsSpecific genomic changesOral premalignancyTherapeutic approachesNovel biomarkersMalignant transformationMicroenvironmental changesCancerProgressionGenomic changesMicroenvironmentAlterationsGenetic changesPremalignancyTherapyLesions
2021
Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
Kumar M, Molkentine D, Molkentine J, Bridges K, Xie T, Yang L, Hefner A, Gao M, Bahri R, Dhawan A, Frederick MJ, Seth S, Abdelhakiem M, Beadle BM, Johnson F, Wang J, Shen L, Heffernan T, Sheth A, Ferris RL, Myers JN, Pickering CR, Skinner HD. Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function. Nature Communications 2021, 12: 6340. PMID: 34732714, PMCID: PMC8566594, DOI: 10.1038/s41467-021-26570-8.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsApoptosisBiomarkers, TumorBRCA1 ProteinCell Line, TumorCREB-Binding ProteinE1A-Associated p300 ProteinGain of Function MutationHistone AcetyltransferasesHomologous RecombinationHumansMaleMice, NudeMutationNeoplasmsProtein DomainsSquamous Cell Carcinoma of Head and NeckXenograft Model Antitumor AssaysBiology of the Radio- and Chemo-Responsiveness in HPV Malignancies
Spiotto MT, Taniguchi CM, Klopp AH, Colbert LE, Lin SH, Wang L, Frederick MJ, Osman AA, Pickering CR, Frank SJ. Biology of the Radio- and Chemo-Responsiveness in HPV Malignancies. Seminars In Radiation Oncology 2021, 31: 274-285. PMID: 34455983, PMCID: PMC8689584, DOI: 10.1016/j.semradonc.2021.02.009.Peer-Reviewed Original ResearchConceptsHPV-positive cancersPotential biological mechanismsHPV-positive cancer cellsHPV-negative cancersCancer cellsImproved clinical outcomesCancer stem cell subpopulationMultiple anatomic sitesHPV-negative cellsG2/M arrestBiological mechanismsHPV MalignanciesLocoregional controlOverall survivalClinical outcomesPreclinical observationsAnatomic sitesHypoxic tumor microenvironmentStem cell subpopulationCancerTumor microenvironmentCell subpopulationsRadiosensitive phaseImpaired DNA damage responseOxidative stressLung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology
Stewart CA, Gay CM, Ramkumar K, Cargill KR, Cardnell RJ, Nilsson MB, Heeke S, Park EM, Kundu ST, Diao L, Wang Q, Shen L, Xi Y, Zhang B, Della Corte CM, Fan Y, Kundu K, Gao B, Avila K, Pickering CR, Johnson FM, Zhang J, Kadara H, Minna JD, Gibbons DL, Wang J, Heymach JV, Byers LA. Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2–Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology. Journal Of Thoracic Oncology 2021, 16: 1821-1839. PMID: 34274504, PMCID: PMC8282443, DOI: 10.1016/j.jtho.2021.07.002.Peer-Reviewed Original ResearchConceptsSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Syndrome coronavirus 2Coronavirus disease 2019SARS-CoV-2Coronavirus 2Disease 2019Coronavirus disease 2019 pathophysiologyMesenchymal transitionSARS-CoV-2 infectionSARS-CoV-2 pathogenesisSARS-CoV-2 receptorTyrosine kinase inhibitor resistanceEGFR tyrosine kinase inhibitor resistanceRegulation of ZEB1Lung cancer model systemsLung cancer modelKinase inhibitor resistanceCancer cell linesACE2 expressionRegulation of ACE2Respiratory virusesCancer model systemsHealthy patientsLow doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu‐opioid receptor
Gorur A, Patiño M, Shi T, Corrales G, Takahashi H, Rangel R, Gleber‐Netto F, Pickering C, Myers JN, Cata JP. Low doses of methylnaltrexone inhibits head and neck squamous cell carcinoma growth in vitro and in vivo by acting on the mu‐opioid receptor. Journal Of Cellular Physiology 2021, 236: 7698-7710. PMID: 34038587, DOI: 10.1002/jcp.30421.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCell Line, TumorCell MovementCell ProliferationEpithelial-Mesenchymal TransitionHead and Neck NeoplasmsHumansMaleMice, Inbred C57BLMice, NudeNaltrexoneNarcotic AntagonistsNeoplasm InvasivenessQuaternary Ammonium CompoundsReceptors, Opioid, muSignal TransductionSquamous Cell Carcinoma of Head and NeckTumor BurdenXenograft Model Antitumor AssaysConceptsMu-opioid receptorsEffects of methylnaltrexoneHNSCC cell linesTumor growthCell linesNeck squamous cell carcinoma growthNeck squamous cell carcinomaDifferent HNSCC cell linesClonogenic activitySquamous cell carcinoma growthSquamous cell carcinomaLung cancer cell linesCyclic adenosine monophosphate levelsTumor-bearing miceAggressive cell behaviorEpithelial-mesenchymal transitionAdenosine monophosphate levelsCancer cell linesCell carcinomaMethylnaltrexoneCarcinoma growthTherapeutic targetLow dosesFaDu cellsMetastasis formationMu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma
Gorur A, Patiño M, Takahashi H, Corrales G, Pickering CR, Gleber-Netto FO, Myers JN, Cata JP. Mu-opioid receptor activation promotes in vitro and in vivo tumor growth in head and neck squamous cell carcinoma. Life Sciences 2021, 278: 119541. PMID: 33930368, DOI: 10.1016/j.lfs.2021.119541.Peer-Reviewed Original ResearchConceptsMu-opioid receptorsMOR activationTumor growthSelective MOR agonist DAMGOMu-opioid receptor activationNeck squamous cell carcinomaSquamous cell carcinoma progressionNeck squamous cell carcinoma progressionMOR agonist DAMGOSquamous cell carcinomaTumorigenesis of HNSCCPotential therapeutic targetVivo tumor growthAgonist DAMGOCell carcinomaSaline 0.9MOR agonistsTherapeutic targetCarcinoma progressionReceptor activationHNSCCVivo studiesColony formationCell linesMe-Phe