2024
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Robles-Oteíza C, Hastings K, Choi J, Sirois I, Ravi A, Expósito F, de Miguel F, Knight J, López-Giráldez F, Choi H, Socci N, Merghoub T, Awad M, Getz G, Gainor J, Hellmann M, Caron É, Kaech S, Politi K. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer. Journal Of Experimental Medicine 2024, 222: e20231106. PMID: 39585348, DOI: 10.1084/jem.20231106.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsNon-small cell lung cancerAcquired resistanceCheckpoint inhibitorsResistant tumorsPatients treated with anti-PD-1/PD-L1 therapyAnti-PD-1/PD-L1 therapyLung cancerResistance to immune checkpoint inhibitorsAssociated with decreased progression-free survivalHypoxia activated pro-drugsTargeting hypoxic tumor regionsTreat non-small cell lung cancerAnti-CTLA-4Anti-PD-1Immune checkpoint inhibitionTumor metabolic featuresProgression-free survivalCell lung cancerResistant cancer cellsHypoxic tumor regionsMHC-II levelsRegions of hypoxiaKnock-outCheckpoint inhibition207 Spatial transcriptomic profiling non-small cell lung cancer reveals potential drivers of CTL exclusion and dysfunction, and identifies novel predictive biomarkers for checkpoint blockade therapy
Cho C, Lopez-Giraldez F, Huang B, He J, Woodard G, Badri T, Kidacki M, Vesely M, Wang G, Ofori-Ntiamoah G, Ng E, Chen L. 207 Spatial transcriptomic profiling non-small cell lung cancer reveals potential drivers of CTL exclusion and dysfunction, and identifies novel predictive biomarkers for checkpoint blockade therapy. 2024, a236-a236. DOI: 10.1136/jitc-2024-sitc2024.0207.Peer-Reviewed Original ResearchIL-1β Induces Human Endothelial Surface Expression of IL-15 by Relieving let-7c-3p Suppression of Protein Translation.
Mullan C, Summer L, Lopez-Giraldez F, Tobiasova Z, Manes T, Yasothan S, Song G, Jane-Wit D, Saltzman W, Pober J. IL-1β Induces Human Endothelial Surface Expression of IL-15 by Relieving let-7c-3p Suppression of Protein Translation. The Journal Of Immunology 2024, 213: 1338-1348. PMID: 39302113, PMCID: PMC11493510, DOI: 10.4049/jimmunol.2400331.Peer-Reviewed Original ResearchIL-15Surface expressionIL-1BIL-15 transcriptsEndothelial cellsCD8 T cell activationExpression of IL-15EC surface expressionIL-15 transpresentationComplement activationGraft endothelial cellsActivity of CTLT cell activationIL-15 mRNAEndothelial surface expressionAbsence of complement activationCultured human endothelial cellsIL-1-mediated activationIL-15RAProtein translationAllograft rejectionRNA polymerase II-mediated transcriptionHuman endothelial cellsSuppression of protein translationmTORC1 Signaling in Brain Endothelial Progenitors Contributes to CCM Pathogenesis
Min W, Qin L, Zhang H, López-Giráldez F, Jiang N, Kim Y, Mohan V, Su M, Murray K, Grutzendler J, Zhou J. mTORC1 Signaling in Brain Endothelial Progenitors Contributes to CCM Pathogenesis. Circulation Research 2024, 135: e94-e113. PMID: 38957991, PMCID: PMC11293987, DOI: 10.1161/circresaha.123.324015.Peer-Reviewed Original ResearchCerebral vascular malformationsEndothelial progenitor cellsBlood-brain barrier integritySingle-cell RNA sequencing analysisDisruption of blood-brain barrier integrityBarrier integrityResident endothelial progenitor cellsRNA sequencing analysisTissue immunofluorescence analysisEndothelial cellsEPC clustersStem cell markersFocal neurological deficitsBrain's neurovascular unitMTOR signalingHuman CCM lesionsMTORC1 signalingBlood-brain barrierCapillary endothelial cellsCCM pathogenesisVascular malformationsLesion signaturesNeurological deficitsCell markersClonal expansionmTORC1 signaling in brain endothelial progenitors contributes to CCM pathogenesis
Min W, Qin L, Zhang H, López-Giráldez F, Kim Y, Jiang N, Mohan VK, Su M, Murray KN, Grutzendler J, Zhou JH. mTORC1 signaling in brain endothelial progenitors contributes to CCM pathogenesis. Circulation Research 2024Peer-Reviewed Original ResearchASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.
Hu B, Wiesehöfer M, de Miguel F, Liu Z, Chan L, Choi J, Melnick M, Arnal Estape A, Walther Z, Zhao D, Lopez-Giraldez F, Wurtz A, Cai G, Fan R, Gettinger S, Xiao A, Yan Q, Homer R, Nguyen D, Politi K. ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts. Cancer Research 2024, 84: 1303-1319. PMID: 38359163, PMCID: PMC11142404, DOI: 10.1158/0008-5472.can-23-0438.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsPatient-derived xenograftsEGFR mutant lung cancerMutant lung cancerPre-treatment tumorsResidual diseaseDrug toleranceLung cancerResidual tumor cells in vivoEGFR mutant lung adenocarcinomaTyrosine kinase inhibitor osimertinibEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitor treatmentTumor cells in vivoMutant lung adenocarcinomaMaximal tumor regressionTranscription factor Ascl1Drug-tolerant cellsTime of maximal responseEvidence of cellsCells in vivoOsimertinib treatmentTumor regressionSingle cell transcriptional profilingTumor cells
2023
LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
Hwang J, Chai P, Nawaz S, Choi J, Lopez-Giraldez F, Hussain S, Bilguvar K, Mane S, Lifton R, Ahmad W, Zhang K, Chung J. LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility. ELife 2023, 12: rp90095. PMID: 38091523, PMCID: PMC10721216, DOI: 10.7554/elife.90095.Peer-Reviewed Original ResearchLRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
Hwang J, Chai P, Nawaz S, Choi J, Lopez-Giraldez F, Hussain S, Bilguvar K, Mane S, Lifton R, Ahmad W, Zhang K, Chung J. LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility. ELife 2023, 12 DOI: 10.7554/elife.90095.3.Peer-Reviewed Original ResearchLineage-specific genes are clustered with HET-domain genes and respond to environmental and genetic manipulations regulating reproduction in Neurospora
Wang Z, Wang Y, Kasuga T, Lopez-Giraldez F, Zhang Y, Zhang Z, Wang Y, Dong C, Sil A, Trail F, Yarden O, Townsend J. Lineage-specific genes are clustered with HET-domain genes and respond to environmental and genetic manipulations regulating reproduction in Neurospora. PLOS Genetics 2023, 19: e1011019. PMID: 37934795, PMCID: PMC10684091, DOI: 10.1371/journal.pgen.1011019.Peer-Reviewed Original ResearchConceptsLineage-specific genesHET domain genesSexual reproductionFunctional roleUnusual carbon sourcesPotential functional roleMating lociAsexual growthGenetic mutantsNeurospora crassaPossible functional roleSexual phaseGenetic manipulationTranscriptomic profilingReproduction regulationGene knockoutPP-1ADV-1Environmental alterationsGenesSexual developmentNeurosporaReproductionCarbon sourceGenetic barrierOrigins of lineage‐specific elements via gene duplication, relocation, and regional rearrangement in Neurospora crassa
Wang Z, Wang Y, Kasuga T, Hassler H, Lopez‐Giraldez F, Dong C, Yarden O, Townsend J. Origins of lineage‐specific elements via gene duplication, relocation, and regional rearrangement in Neurospora crassa. Molecular Ecology 2023 PMID: 37843462, DOI: 10.1111/mec.17168.Peer-Reviewed Original ResearchLineage-specific genesGene duplicationNew genesLineage-specific elementsWeighted gene correlation network analysisRecent gene duplicationNon-coding DNACell wall integrityCo-regulatory modulesGene correlation network analysisNon-coding sequencesCorrelation network analysisAntifungal toxinsGene syntenyNeurospora speciesGenus NeurosporaEvolutionary biologistsSuch cladesRegulatory machinerySequence repeatsModel speciesAncestral statusNeurospora crassaTranscriptomic dataDiverse functionsMicroRNA-1 protects the endothelium in acute lung injury
Korde A, Haslip M, Pednekar P, Khan A, Chioccioli M, Mehta S, Lopez-Giraldez F, Bermejo S, Rojas M, Dela Cruz C, Matthay M, Pober J, Pierce R, Takyar S. MicroRNA-1 protects the endothelium in acute lung injury. JCI Insight 2023, 8: e164816. PMID: 37737266, PMCID: PMC10561733, DOI: 10.1172/jci.insight.164816.Peer-Reviewed Original ResearchConceptsAcute respiratory distress syndromeAcute lung injuryVascular endothelial growth factorAngiopoietin-2Lung injuryAcute injuryMiR-1MicroRNA-1Endothelial cell-specific overexpressionSevere endothelial dysfunctionRespiratory distress syndromeSurvival of miceIntrinsic protective effectContext of injuryCell-specific overexpressionEndothelial growth factorFamily member 3Pneumonia cohortMiR-1 targetsEndothelial dysfunctionDistress syndromeBarrier dysfunctionCapillary leakProtective effectSevere formMultiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts
Kundishora A, Allington G, McGee S, Mekbib K, Gainullin V, Timberlake A, Nelson-Williams C, Kiziltug E, Smith H, Ocken J, Shohfi J, Allocco A, Duy P, Elsamadicy A, Dong W, Zhao S, Wang Y, Qureshi H, DiLuna M, Mane S, Tikhonova I, Fu P, Castaldi C, López-Giráldez F, Knight J, Furey C, Carter B, Haider S, Moreno-De-Luca A, Alper S, Gunel M, Millan F, Lifton R, Torene R, Jin S, Kahle K. Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts. Nature Medicine 2023, 29: 667-678. PMID: 36879130, DOI: 10.1038/s41591-023-02238-2.Peer-Reviewed Original ResearchConceptsArachnoid cystCerebral arachnoid cystsDe novo variantsAC pathogenesisDevelopmental brain lesionsStructural brain diseaseAppropriate clinical contextPatients' medical recordsDamaging de novo variantsMedical recordsClinical severityBrain lesionsHealthy individualsAC subtypesBrain diseasesGenetic testingNeurodevelopmental pathologyClinical contextPathogenesisPatient phenotypesNeurodevelopmental programsNovo variantsRNA sequencing transcriptomeHuman brainCystsHYDIN Variants Are a Common Cause of Primary Ciliary Dyskinesia in French Canadians.
Shapiro A, Sillon G, D'Agostino D, Baret L, López-Giráldez F, Mane S, Leigh M, Davis S, Knowles M, Zariwala M. HYDIN Variants Are a Common Cause of Primary Ciliary Dyskinesia in French Canadians. Annals Of The American Thoracic Society 2023, 20: 140-144. PMID: 36112114, PMCID: PMC9819264, DOI: 10.1513/annalsats.202203-253rl.Peer-Reviewed Original Research
2022
Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer
Adua S, Arnal-Estapé A, Zhao M, Qi B, Liu Z, Kravitz C, Hulme H, Strittmatter N, López-Giráldez F, Chande S, Albert A, Melnick M, Hu B, Politi K, Chiang V, Colclough N, Goodwin R, Cross D, Smith P, Nguyen D. Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer. Nature Communications 2022, 13: 7690. PMID: 36509758, PMCID: PMC9744876, DOI: 10.1038/s41467-022-34889-z.Peer-Reviewed Original ResearchConceptsGene expression programsRas homolog family member ACancer cellsFamily member AEpidermal growth factor receptorExpression programsMetastatic cancer cellsSRF signalingGrowth factor receptorTumor microenvironmentLung cancerFunctional linkExtracellular lamininDrug-resistant cancer cellsMutant non-small cell lung cancerNon-small cell lung cancerCentral nervous system relapseMolecular studiesMember AEGFR-mutant lung cancerFactor receptorNervous system relapseCell lung cancerDisseminated tumor cellsBrain tumor microenvironmentMitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
Zhang H, Li B, Huang Q, López-Giráldez F, Tanaka Y, Lin Q, Mehta S, Wang G, Graham M, Liu X, Park I, Eichmann A, Min W, Zhou J. Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas. Nature Communications 2022, 13: 7637. PMID: 36496409, PMCID: PMC9741628, DOI: 10.1038/s41467-022-35262-w.Peer-Reviewed Original ResearchConceptsMitochondrial dysfunctionThioredoxin 2Single-cell RNA-seq analysisRNA-seq analysisMutant miceNuclear genesMitochondrial proteinsMitochondrial localizationHuman retinal diseasesTranscriptional factorsGene expressionMutant retinasMitochondrial activityExtracellular matrixNovel mechanismVascular maturationArteriovenous malformationsGenetic deficiencyVessel growthSmad2Mouse retinaVascular malformationsMechanistic studiesBasement membraneRetinal vascular malformationsDifferential Expression of Cell Wall Remodeling Genes Is Part of the Dynamic Phase-Specific Transcriptional Program of Conidial Germination of Trichoderma asperelloides
Gortikov M, Yakubovich E, Wang Z, López-Giráldez F, Tu Y, Townsend JP, Yarden O. Differential Expression of Cell Wall Remodeling Genes Is Part of the Dynamic Phase-Specific Transcriptional Program of Conidial Germination of Trichoderma asperelloides. Journal Of Fungi 2022, 8: 854. PMID: 36012842, PMCID: PMC9410309, DOI: 10.3390/jof8080854.Peer-Reviewed Original ResearchPolar growthTranscript abundanceConidial germinationGlucanase-encoding geneOnset of germinationTranscriptional hubsTranscriptional programsTrichoderma asperelloidesHyphal growthTranscriptional profilesDevelopmental eventsChitin synthaseHost recognitionDifferential expressionGerminationSpecific membersDormant conidiaFirst branchingGenomeGenesInitial branchingAbundanceNetwork analysisExpressionMorphological progressionSecondary Metabolism Gene Clusters Exhibit Increasingly Dynamic and Differential Expression during Asexual Growth, Conidiation, and Sexual Development in Neurospora crassa
Wang Z, Lopez-Giraldez F, Slot J, Yarden O, Trail F, Townsend JP. Secondary Metabolism Gene Clusters Exhibit Increasingly Dynamic and Differential Expression during Asexual Growth, Conidiation, and Sexual Development in Neurospora crassa. MSystems 2022, 7: e00232-22. PMID: 35638725, PMCID: PMC9239088, DOI: 10.1128/msystems.00232-22.Peer-Reviewed Original ResearchConceptsSM clustersComparative genomicsSecondary metabolitesAsexual growthN. crassaNeurospora crassaSecondary metabolism gene clustersSexual developmentDevelopmental stagesSecondary metabolite clustersComparative genomic analysisExtensive transcriptomic dataGene expression patternsEnvironmental conditionsFungal toxin productionLevel of RNASMC genesLife cycleRegulatory switchComputational annotationGene clusterEnvironmental signalsMetabolite clustersGenomic analysisKnockout phenotypesWhole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer
Liu Y, Helgadottir HT, Kharaziha P, Choi J, López-Giráldez F, Mane SM, Höiom V, Juhlin CC, Larsson C, Bajalica-Lagercrantz S. Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer. Biomedicines 2022, 10: 1004. PMID: 35625741, PMCID: PMC9138793, DOI: 10.3390/biomedicines10051004.Peer-Reviewed Original ResearchHereditary breast cancerBreast cancerWhole-exome sequencingBreast cancer susceptibilityHereditary cancer-related genesHigh-risk cancer genesFamilial casesCancer susceptibilityAutosomal dominant inheritance patternDominant inheritance patternPrevalent malignancyFamily historyCancer-related genesCancer-related pathwaysPathogenic variantsProtein expression analysisGermline variantsCancerFunction variantsExome sequencingRecurrent genesRisk variantsInheritance patternMinor allele frequencyExonic variantsWhole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia
Dong W, Wong KHY, Liu Y, Levy-Sakin M, Hung WC, Li M, Li B, Jin SC, Choi J, Lopez-Giraldez F, Vaka D, Poon A, Chu C, Lao R, Balamir M, Movsesyan I, Malloy MJ, Zhao H, Kwok PY, Kane JP, Lifton RP, Pullinger CR. Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia. Journal Of Lipid Research 2022, 63: 100209. PMID: 35460704, PMCID: PMC9126845, DOI: 10.1016/j.jlr.2022.100209.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingCandidate genesDamaging variantsGenome-wide association studiesGenome-wide significanceDamaging rare variantsCandidate gene listGene burden testingHDL-C levelsGene variantsGene listsAssociation studiesLDLR geneGenesBurden testingCancer biologySequencingFunction variantsABCA1Mean HDL-C levelsRare variantsDiscovery studiesCoronary heart diseaseHDL deficiencyRisk of cancerArhGEF12 activates Rap1A and not RhoA in human dermal microvascular endothelial cells to reduce tumor necrosis factor‐induced leak
Khan A, Ni W, Baltazar T, Lopez‐Giraldez F, Pober JS, Pierce RW. ArhGEF12 activates Rap1A and not RhoA in human dermal microvascular endothelial cells to reduce tumor necrosis factor‐induced leak. The FASEB Journal 2022, 36: e22254. PMID: 35294066, PMCID: PMC9103844, DOI: 10.1096/fj.202101873rr.Peer-Reviewed Original Research