Featured Publications
ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer
Xu Y, Yang Y, Wang Z, Sjostrom M, Jiang Y, Tang Y, Cheng S, Deng S, Wang C, Gonzalez J, Johnson N, Li X, Li X, Metang L, Mukherji A, Xu Q, Tirado C, Wainwright G, Yu X, Barnes S, Hofstad M, Chen Y, Zhu H, Hanker A, Raj G, Zhu G, He H, Wang Z, Arteaga C, Liang H, Feng F, Wang Y, Wang T, Mu P. ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer. Cancer Discovery 2024, 14: 1496-1521. PMID: 38591846, PMCID: PMC11285331, DOI: 10.1158/2159-8290.cd-23-0539.Peer-Reviewed Original ResearchConceptsLineage plasticityTherapy resistanceProstate cancerCancer cellsAndrogen receptorResistance to AR-targeted therapiesLuminal lineageAR-targeted therapiesOvercome therapy resistanceTransition of cancer cellsEpigenetic regulatory machineryBona fide coactivatorTherapy responseAR signalingEpigenetic rewiringDrug resistanceTherapeutic strategiesEpigenetic reprogrammingProstateTherapyCancerPhenotypic plasticityRegulatory machineryAndrogenTranscriptional programsUBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance
Rodriguez Tirado C, Wang C, Li X, Deng S, Gonzalez J, Johnson N, Xu Y, Metang L, Sundar Rajan M, Yang Y, Yin Y, Hofstad M, Raj G, Zhang S, Lemoff A, He W, Fan J, Wang Y, Wang T, Mu P. UBE2J1 is the E2 ubiquitin-conjugating enzyme regulating androgen receptor degradation and antiandrogen resistance. Oncogene 2023, 43: 265-280. PMID: 38030789, PMCID: PMC10798893, DOI: 10.1038/s41388-023-02890-5.Peer-Reviewed Original ResearchConceptsAberrant androgen receptorProstate cancerAR ubiquitinationAR degradationAntiandrogen therapyResistance to antiandrogen therapyE2 ubiquitin-conjugating enzymeEnhanced AR signalingAndrogen receptor degradersAR protein levelsProstate cancer patientsUbiquitin-conjugating enzymeResistant tumorsPCa tumorsAR signalingAndrogen receptorAntiandrogen treatmentAntiandrogen resistanceAR proteinReceptor degradationProtein levelsOncogenic proteinsTumorTherapyProtein degradation processLoss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer
Li X, Wang Y, Deng S, Zhu G, Wang C, Johnson N, Zhang Z, Tirado C, Xu Y, Metang L, Gonzalez J, Mukherji A, Ye J, Yang Y, Peng W, Tang Y, Hofstad M, Xie Z, Yoon H, Chen L, Liu X, Chen S, Zhu H, Strand D, Liang H, Raj G, He H, Mendell J, Li B, Wang T, Mu P. Loss of SYNCRIP unleashes APOBEC-driven mutagenesis, tumor heterogeneity, and AR-targeted therapy resistance in prostate cancer. Cancer Cell 2023, 41: 1427-1449.e12. PMID: 37478850, PMCID: PMC10530398, DOI: 10.1016/j.ccell.2023.06.010.Peer-Reviewed Original ResearchConceptsProstate cancerTherapy resistanceTumor heterogeneityTumor mutational burdenCell-intrinsic mechanismsPromote tumor heterogeneityMutational burdenTargeted therapyDriver mutationsPCa cellsCancer cellsHuman cancersMutated genesCancerMutational signaturesProstateTumorTherapyFOXA1APOBEC proteinsAPOBEC3BEP300Molecular brakeMutationsSYNCRIPEctopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance
Deng S, Wang C, Wang Y, Xu Y, Li X, Johnson N, Mukherji A, Lo U, Xu L, Gonzalez J, Metang L, Ye J, Tirado C, Rodarte K, Zhou Y, Xie Z, Arana C, Annamalai V, Liu X, Vander Griend D, Strand D, Hsieh J, Li B, Raj G, Wang T, Mu P. Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance. Nature Cancer 2022, 3: 1071-1087. PMID: 36065066, PMCID: PMC9499870, DOI: 10.1038/s43018-022-00431-9.Peer-Reviewed Original ResearchConceptsJAK-STAT activationJanus kinase (JAK)-signal transducerTherapy resistanceLineage plasticityTranscriptional programsJAK-STATAR-targeted therapiesLineage programsLineagesMolecular mechanismsTranscriptomic aberrationsPharmaceutical inhibitionProstate cancerTargeted therapyStem-likeTherapeutic targetTherapyLoss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation
Zhang Z, Zhou C, Li X, Barnes S, Deng S, Hoover E, Chen C, Lee Y, Zhang Y, Wang C, Metang L, Wu C, Tirado C, Johnson N, Wongvipat J, Navrazhina K, Cao Z, Choi D, Huang C, Linton E, Chen X, Liang Y, Mason C, de Stanchina E, Abida W, Lujambio A, Li S, Lowe S, Mendell J, Malladi V, Sawyers C, Mu P. Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation. Cancer Cell 2020, 37: 584-598.e11. PMID: 32220301, PMCID: PMC7292228, DOI: 10.1016/j.ccell.2020.03.001.Peer-Reviewed Original ResearchMeSH KeywordsAndrogen AntagonistsAnimalsApoptosisBiomarkers, TumorCell ProliferationChromatinDNA HelicasesDNA-Binding ProteinsDrug Resistance, NeoplasmGene Expression Regulation, NeoplasticHigh-Throughput Screening AssaysHumansMaleMiceProstatic Neoplasms, Castration-ResistantReceptors, AndrogenRNA, Small InterferingTranscription FactorsTumor Cells, CulturedXenograft Model Antitumor AssaysConceptsAntiandrogen resistanceChromatin dysregulationCHD1 lossProstate cancerGenomic copy number alterationsRNA-seq analysisResistance to hormonal therapyCopy number alterationsAR-targeted therapiesMetastatic prostate cancerATAC-seqClosed chromatinRNA-seqTranscriptional plasticityTranscription factorsFunctional screeningTranscriptomic changesMechanisms of resistanceHormone therapyLineage programsChromatinCHD1Global changeIntegrated analysisTherapySOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer
Mu P, Zhang Z, Benelli M, Karthaus W, Hoover E, Chen C, Wongvipat J, Ku S, Gao D, Cao Z, Shah N, Adams E, Abida W, Watson P, Prandi D, Huang C, de Stanchina E, Lowe S, Ellis L, Beltran H, Rubin M, Goodrich D, Demichelis F, Sawyers C. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 2017, 355: 84-88. PMID: 28059768, PMCID: PMC5247742, DOI: 10.1126/science.aah4307.Peer-Reviewed Original ResearchConceptsLineage plasticityRB1 functionHuman prostate cancer modelProstate cancer modelLoss of TP53Basal-like cellsTumor suppressor geneTranscription factor Sox2Antiandrogen therapyProstate cancerInhibiting Sox2 expressionLineage switchAntiandrogen resistanceCancer modelsTumor cellsSuppressor geneSOX2 expressionIncreased expressionTP53TumorCell lineagesCellular plasticityIn vitroPhenotypic shiftCancer
2023
The Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer.
Li X, Mu P. The Critical Interplay of CAF Plasticity and Resistance in Prostate Cancer. Cancer Research 2023, 83: 2990-2992. PMID: 37504898, DOI: 10.1158/0008-5472.can-23-2260.Commentaries, Editorials and LettersConceptsCastration-resistant prostate cancerAndrogen deprivation therapyProstate cancerAndrogen receptorCastration-resistant prostate cancer developmentDevelopment of castration-resistant prostate cancerGenetically engineered mouse modelsMyofibroblastic cancer-associated fibroblastsOvercome treatment resistanceCancer-associated fibroblastsIncreased tumor heterogeneityDeprivation therapyCRPC developmentProstate tumorsTumor microenvironmentLineage plasticityTreatment resistanceStromal compartmentStandard treatmentTumor heterogeneityCancer recurrenceDrug resistanceDisease progressionMouse modelSingle-cell RNA sequencing
2022
The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer
Lo U, Chen Y, Cen J, Deng S, Luo J, Zhau H, Ho L, Lai C, Mu P, Chung L, Hsieh J. The driver role of JAK‐STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy‐ and castration‐resistant prostate cancer. Clinical And Translational Medicine 2022, 12: e978. PMID: 35908276, PMCID: PMC9339240, DOI: 10.1002/ctm2.978.Peer-Reviewed Original ResearchConceptsCastration-resistant prostate cancerProstate cancerCancer stem cellsActivation of JAKJAK-STAT signalingGene set enrichment analysisJAK-STAT1 pathwaySTAT1 inhibitorAcquisition of stemness propertiesProstate cancer cell linesProstate cancer stemnessAssociated with cancer stem cellsIn vivo anti-tumor activityMetastatic prostate cancerTumor-initiating capabilityJAK-STATProstasphere assayDownstream effectorsIngenuity PathwayGenetic manipulationCSC genesBioinformatics analysisEnrichment analysisJAK-STAT1Signaling pathway
2021
Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview.
Blatt E, Kopplin N, Kumar S, Mu P, Conzen S, Raj G. Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview. Endocrine Related Cancer 2021, 28: r31-r46. PMID: 33263560, PMCID: PMC8218927, DOI: 10.1530/erc-20-0272.Peer-Reviewed Original ResearchConceptsProstate cancerHormone-dependent cancersBreast cancerTherapy resistanceAndrogen receptorMechanisms of endocrine therapy resistanceTherapeutic strategiesTherapy-resistant prostate cancerEndocrine therapy resistanceAdvanced prostate cancerTherapy-resistant tumorsNuclear receptorsMechanisms of resistancePotential therapeutic strategyEndocrine therapyMetastatic patientsAntiestrogen resistanceOncogene addictionClinical benefitTumor typesEstrogen receptorFrequent mechanismCancerReceptorsAugmented activity
2020
Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer
Zhang Z, Karthaus W, Lee Y, Gao V, Wu C, Russo J, Liu M, Mota J, Abida W, Linton E, Lee E, Barnes S, Chen H, Mao N, Wongvipat J, Choi D, Chen X, Zhao H, Manova-Todorova K, de Stanchina E, Taplin M, Balk S, Rathkopf D, Gopalan A, Carver B, Mu P, Jiang X, Watson P, Sawyers C. Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer. Cancer Cell 2020, 38: 279-296.e9. PMID: 32679108, PMCID: PMC7472556, DOI: 10.1016/j.ccell.2020.06.005.Peer-Reviewed Original ResearchMeSH KeywordsAndrogen AntagonistsAnimalsCancer-Associated FibroblastsCell Line, TumorCell ProliferationCells, CulturedDrug Resistance, NeoplasmGene Expression ProfilingGene Expression Regulation, NeoplasticHumansKaplan-Meier EstimateMaleMice, SCIDNeuregulin-1Prostatic NeoplasmsTumor MicroenvironmentXenograft Model Antitumor AssaysConceptsCancer-associated fibroblastsProstate cancerAntiandrogen resistanceNeuregulin-1Second-generation antiandrogen therapyResistance to hormonal therapyCastration-resistant prostate cancerTreat advanced prostate cancerProstate organoid culturesSecond-generation antiandrogensAdvanced prostate cancerActivation of HER3Antiandrogen therapyHormone therapyHormone deprivationPharmacological blockadeTargeted therapyParacrine mechanismsTumor cellsMouse modelProstateClinical testingOrganoid culturesTherapyCancer
2019
The paracrine induction of prostate cancer progression by caveolin-1
Lin C, Yun E, Lo U, Tai Y, Deng S, Hernandez E, Dang A, Chen Y, Saha D, Mu P, Lin H, Li T, Shen T, Lai C, Hsieh J. The paracrine induction of prostate cancer progression by caveolin-1. Cell Death & Disease 2019, 10: 834. PMID: 31685812, PMCID: PMC6828728, DOI: 10.1038/s41419-019-2066-3.Peer-Reviewed Original ResearchConceptsCastration-resistant prostate cancerCancer stem cellsTumor-derived exosomesProstate cancerCav-1Cancer progressionSubpopulation of cancer stem cellsAssociated with stem cell phenotypeCancer immune evasionProstate cancer progressionStem cell capabilitiesStem cell phenotypePromote cancer developmentPresence of Cav-1Heterogeneous cancer cell populationsCancer cell populationsNeuroendocrine differentiationNeuroendocrine transdifferentiationEpithelial-mesenchymal transitionNFkB signaling pathwayTherapeutic resistanceTumor cellsImmune evasionChemotherapeutic resistanceParacrine induction
2017
Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance
Ku S, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich Z, Goodrich M, Labbé D, Gomez E, Wang J, Long H, Xu B, Brown M, Loda M, Sawyers C, Ellis L, Goodrich D. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 2017, 355: 78-83. PMID: 28059767, PMCID: PMC5367887, DOI: 10.1126/science.aah4199.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAndrogen AntagonistsAnimalsCell Line, TumorCell LineageCell PlasticityDrug Resistance, NeoplasmEnhancer of Zeste Homolog 2 ProteinEpigenesis, GeneticHumansMaleMiceMutationNeoplasm MetastasisNeoplasms, ExperimentalNeuroendocrine TumorsProstatic NeoplasmsPTEN PhosphohydrolaseRetinoblastoma-Like Protein p107SOXB1 Transcription FactorsTumor Suppressor Protein p53ConceptsAntiandrogen therapyLineage plasticityClinical responses to antiandrogen therapyResistance to antiandrogen therapyMouse modelMetastasis of prostatic adenocarcinomaResponse to antiandrogen therapyAndrogen receptor expressionProstate cancer progressionLoss of Trp53Lineage marker expressionVariant histologyProstatic adenocarcinomaRB1 lossProstate cancerReceptor expressionPTEN mutationsAntiandrogen resistanceTherapeutic resistanceMouse tumorsGene expression profilesNeuroendocrine variantsReprogramming factorsProstateHuman tumors