Tumor lineage plasticity(LP)is an emerging hallmark of cancer progression.Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids,we identified bromodomain protei...Tumor lineage plasticity(LP)is an emerging hallmark of cancer progression.Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids,we identified bromodomain protein BRD4 as a crucial player.Integrated ChIP-seq and RNA-seq analysis of tumors revealed,for the first time,that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis,axonogenesis,EMT and stem cells and key drivers such as POU3F2(BRN2),ASCL1/2,NeuroD1,SOX2/9,RUNX1/2 and DLL3.Interestingly,BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1.Significantly,we demonstrated that BRD4 inhibitor AZD5153,currently at clinical development,possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer(NEPC)and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action(MOA)by AZD5153.Together,our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.展开更多
Prostate cancer is the most commonly diagnosed and the second-leading cause of cancer-related mortality in men worldwide,especially in Western counties.Therapeutic resistance of prostate cancer remains a major challen...Prostate cancer is the most commonly diagnosed and the second-leading cause of cancer-related mortality in men worldwide,especially in Western counties.Therapeutic resistance of prostate cancer remains a major challenge in modern oncology,necessitating new scientific understanding of the disease and devising new targeting strate-gies.This review examines the intricate relationship between transcriptional and epigenetic reprogramming,lineage plasticity,and therapeutic resistance in prostate cancer.Prostate cancer cells can adapt and resist vari-ous treatment modalities,including androgen deprivation therapy(ADT)and next-generation androgen receptor(AR)signaling inhibitors(ARSI),through transcriptional reprogramming and epigenetic modifications.Lineage plasticity,the ability of cells to alter their cellular identities,further drives treatment resistance.Moreover,can-cer cells can adjust their gene expression profiles to evade therapy by activating key transcription factors and epigenetic regulatory mechanisms such as DNA methylation,histone modification,and non-coding RNA expres-sion.The article concludes by discussing new therapeutic strategies targeting these reprogramming and plasticity mechanisms,emphasizing the importance of combination therapy and precision medicine in developing more effective treatments for advanced prostate cancer.展开更多
Objective:Prostate cancer(PCa)is a complex disease characterized by diverse cellular ecosystems within the tumor microenvironment(TME)and high tumor heterogeneity,which challenges clinically stratified management and ...Objective:Prostate cancer(PCa)is a complex disease characterized by diverse cellular ecosystems within the tumor microenvironment(TME)and high tumor heterogeneity,which challenges clinically stratified management and reinforces the need for novel strategies to fight against castration-resistant PCa(CRPC).Methods:We performed single-cell RNA sequencing(scRNA-seq)on 10 untreated primary PCa tissues and integrated public scRNA-seq resources from three normal prostate tissues,two untreated primary PCa tissues,and six CRPC tumors to portray a comprehensive cellular and molecular interaction atlas of PCa.We further integrated the single-cell and bulk transcriptomes of PCa to establish a molecular classification system.Results:scRNA-seq profiles revealed substantial inter-and intra-tumoral heterogeneity across different cell subpopulations in untreated PCa and CRPC tumors.In the malignant epithelial reservoir,cells evolved along decoupled paths in treatment-naive PCa and CRPC tumors,and distinct transcriptional reprogramming processes were activated,highlighting anti-androgen therapy-induced lineage plasticity.Based on the specifically expressed markers of the epithelial subpopulations,we conducted unsupervised clustering analysis in The Cancer Genome Atlas prostate adenocarcinoma(TCGA-PRAD)cohort and identified three molecularly and clinically distinct subtypes.The C1 subtype,characterized by high enrichment of CRPC-enriched epithelial cells,had a high risk of rapid development of anti-androgen resistance and might require active surveillance and additional promising intervention treatments,such as integrin A3(ITGA3)+integrin B1(ITGB1)inhibition.The C2 subtype resembled the immune-modulated subtype that was most likely to benefit from anti-LAG3 immunotherapy.The C3 subtype had a favorable prognosis.Conclusions:Our study provides a comprehensive and high-resolution landscape of the intricate architecture of the PCa TME,and our trichotomic molecular taxonomy could help facilitate precision oncology.展开更多
Dear Editor,Recent advancements in cancer drug discovery have shifted focus toward targeting the intrinsic properties of tumor cells,such as lineage plasticity and epigenetic regulation(Hanahan,2022;Yuan et al.,2019)....Dear Editor,Recent advancements in cancer drug discovery have shifted focus toward targeting the intrinsic properties of tumor cells,such as lineage plasticity and epigenetic regulation(Hanahan,2022;Yuan et al.,2019).This approach aims to induce re-differentiation or reprogramming of dedifferentiated cells,offering significant clinical potential for improving cancer treatment outcomes(Gong et al.,2019).展开更多
Treatment-induced neuroendocrine prostate cancer(NEPC)represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition,posing a significant clinical challenge.In a recent landmark st...Treatment-induced neuroendocrine prostate cancer(NEPC)represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition,posing a significant clinical challenge.In a recent landmark study,Wang et al.introduced an innovative internal Z-score based approach to comprehensively characterize the transcription factor(TF)landscape in prostate cancer progression,uncovering distinct TF profiles associated with adenocarcinoma and NEPC lineages.Notably,the study proposes a three-phase model of NEPC transdifferentiation-comprising de-differentiation,dormancy,and re-differentiation-revealing dynamic shifts in TF expression that underpin lineage plasticity and therapeutic resistance.This commentary critically evaluates the methodological advancements,the functional significance of the identified TF signatures,and the broader implications of these findings for developing novel therapeutic strategies.By delineating the molecular events driving the transition from androgen receptor(AR)-dependent adenocarcinoma to treatment-resistant NEPC,this work underscores the potential of targeting early and dormant phases of transdifferentiation to improve patient outcomes.展开更多
Prostate cancer remains a major health problem,with its incidence ranking second among male malignancies worldwide.Recent studies have highlighted the critical role of the SOX family transcription factors,especially S...Prostate cancer remains a major health problem,with its incidence ranking second among male malignancies worldwide.Recent studies have highlighted the critical role of the SOX family transcription factors,especially SOX2,in prostate cancer pathogenesis.SOX2 regulates the fate of cancer stem/progenitor cells,contributing to tumor initiation,development,and metastasis.Elevated SOX2 levels have been detected in prostate cancer tissues and are associated with higher tumor grade,aggressive phenotype,and poor prognosis.SOX2 also impacts various tumor biological behaviors,including cell proliferation,invasion,metastasis,resistance to apoptosis,and treatment resistance.This review highlights the role of SOX proteins in prostate cancer,focusing on the molecular mechanisms by which SOX2 drives cancer progression,elucidating the mechanisms controlling its activity,and emphasizing its potential as a therapeutic target.展开更多
The mucin 1(MUC1)gene emerged in mammals to afford protection of barrier epithelial tissues from the external environment.MUC1 encodes a transmembrane C-terminal(MUC1-C)subunit that is activated by loss of homeostasis...The mucin 1(MUC1)gene emerged in mammals to afford protection of barrier epithelial tissues from the external environment.MUC1 encodes a transmembrane C-terminal(MUC1-C)subunit that is activated by loss of homeostasis and induces inflammatory,proliferative,and remodeling pathways associated with wound repair.As a consequence,chronic activation of MUC1-C promotes lineage plasticity,epigenetic reprogramming,and carcinogenesis.In driving cancer progression,MUC1-C is imported into the nucleus,where it induces NF-κB inflammatory signaling and the epithelial-mesenchymal transition(EMT).MUC1-C represses gene expression by activating(i)DNA methyltransferase 1(DNMT1)and DNMT3b,(ii)Polycomb Repressive Complex 1(PRC1)and PRC2,and(iii)the nucleosome remodeling and deacetylase(NuRD)complex.PRC1/2-mediated gene repression is counteracted by the SWI/SNF chromatin remodeling complexes.MUC1-C activates the SWI/SNF BAF and PBAF complexes in cancer stem cell(CSC)models with the induction of genome-wide differentially accessible regions and expressed genes.MUC1-C regulates chromatin accessibility of enhancer-like signatures in association with the induction of the Yamanaka pluripotency factors and recruitment of JUN and BAF,which promote increases in histone activation marks and opening of chromatin.These and other findings described in this review have uncovered a pivotal role for MUC1-C in integrating lineage plasticity and epigenetic reprogramming,which are transient in wound repair and sustained in promoting CSC progression.展开更多
Treatment-induced neuroendocrine prostate cancer(t-NEPC)is a lethal subtype of castration-resistant prostate cancer(CRPC)characterized by unique pathological features and molecular changes,including the loss of an-dro...Treatment-induced neuroendocrine prostate cancer(t-NEPC)is a lethal subtype of castration-resistant prostate cancer(CRPC)characterized by unique pathological features and molecular changes,including the loss of an-drogen receptor(AR)activities and the gain of neuroendocrine gene expression.The incidence of t-NEPC has increased substantially in the last decade,in up to 20%of CRPC cases,largely due to intensive treatment of advanced prostate cancer(PCa)with AR pathway inhibitors(ARPi).While genomic alterations between CRPC and t-NEPC are largely conserved,their epigenetic programs are markedly distinct.The molecular mechanisms underlying the neuroendocrine transformation(NET)of PCa are rapidly emerging.Here,we first briefly summa-rize the genetic drivers of t-NEPC and then comprehensively review 2D and 3D chromatin alterations,including changes in DNA methylation,histone modifications,chromatin accessibility,and 3D chromatin organization,during NET of PCa.We then review key molecular regulators,including lineage-specific transcription factors and chromatin modifiers,of such epigenetic programs.Lastly,we discuss evidence that suggests a mixed model of clonal selection and transformation that underlies NEPC progression.展开更多
基金supported in part by grants from the NIH(R01 CA259081 and R01 CA224900,USA)the Prostate Cancer Foundation(16CHAL02,USA),the US Department of DefensePCRP(PC200522,USA)+1 种基金the US Department of Veterans Affairs,Office of Research and Development BL&D(I01 BX004271,USA)H-WC.The UCDCCC GSR is supported by the NCI Cancer Center Support Grant(NCI P30CA093373,USA).
文摘Tumor lineage plasticity(LP)is an emerging hallmark of cancer progression.Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids,we identified bromodomain protein BRD4 as a crucial player.Integrated ChIP-seq and RNA-seq analysis of tumors revealed,for the first time,that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis,axonogenesis,EMT and stem cells and key drivers such as POU3F2(BRN2),ASCL1/2,NeuroD1,SOX2/9,RUNX1/2 and DLL3.Interestingly,BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1.Significantly,we demonstrated that BRD4 inhibitor AZD5153,currently at clinical development,possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer(NEPC)and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action(MOA)by AZD5153.Together,our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.
文摘Prostate cancer is the most commonly diagnosed and the second-leading cause of cancer-related mortality in men worldwide,especially in Western counties.Therapeutic resistance of prostate cancer remains a major challenge in modern oncology,necessitating new scientific understanding of the disease and devising new targeting strate-gies.This review examines the intricate relationship between transcriptional and epigenetic reprogramming,lineage plasticity,and therapeutic resistance in prostate cancer.Prostate cancer cells can adapt and resist vari-ous treatment modalities,including androgen deprivation therapy(ADT)and next-generation androgen receptor(AR)signaling inhibitors(ARSI),through transcriptional reprogramming and epigenetic modifications.Lineage plasticity,the ability of cells to alter their cellular identities,further drives treatment resistance.Moreover,can-cer cells can adjust their gene expression profiles to evade therapy by activating key transcription factors and epigenetic regulatory mechanisms such as DNA methylation,histone modification,and non-coding RNA expres-sion.The article concludes by discussing new therapeutic strategies targeting these reprogramming and plasticity mechanisms,emphasizing the importance of combination therapy and precision medicine in developing more effective treatments for advanced prostate cancer.
基金supported by Shanghai Science and Technology Commission,China(No.21S11902100)Shanghai Municipal Health Commission Scientific Research Project(No.202140308)+3 种基金Clinical Research Project of Tongji Hospital of Tongji University[No.ITJ(ZD)2209]Shanghai Tongji Hospital National Natural Science Foundation Cultivation Project(No.GJPY2216)Shanghai Medical Innovation Research Special Foundation(No.23Y11908800)CSCO-Haosen Oncology Research Fund(No.Y-HS202301-0096).
文摘Objective:Prostate cancer(PCa)is a complex disease characterized by diverse cellular ecosystems within the tumor microenvironment(TME)and high tumor heterogeneity,which challenges clinically stratified management and reinforces the need for novel strategies to fight against castration-resistant PCa(CRPC).Methods:We performed single-cell RNA sequencing(scRNA-seq)on 10 untreated primary PCa tissues and integrated public scRNA-seq resources from three normal prostate tissues,two untreated primary PCa tissues,and six CRPC tumors to portray a comprehensive cellular and molecular interaction atlas of PCa.We further integrated the single-cell and bulk transcriptomes of PCa to establish a molecular classification system.Results:scRNA-seq profiles revealed substantial inter-and intra-tumoral heterogeneity across different cell subpopulations in untreated PCa and CRPC tumors.In the malignant epithelial reservoir,cells evolved along decoupled paths in treatment-naive PCa and CRPC tumors,and distinct transcriptional reprogramming processes were activated,highlighting anti-androgen therapy-induced lineage plasticity.Based on the specifically expressed markers of the epithelial subpopulations,we conducted unsupervised clustering analysis in The Cancer Genome Atlas prostate adenocarcinoma(TCGA-PRAD)cohort and identified three molecularly and clinically distinct subtypes.The C1 subtype,characterized by high enrichment of CRPC-enriched epithelial cells,had a high risk of rapid development of anti-androgen resistance and might require active surveillance and additional promising intervention treatments,such as integrin A3(ITGA3)+integrin B1(ITGB1)inhibition.The C2 subtype resembled the immune-modulated subtype that was most likely to benefit from anti-LAG3 immunotherapy.The C3 subtype had a favorable prognosis.Conclusions:Our study provides a comprehensive and high-resolution landscape of the intricate architecture of the PCa TME,and our trichotomic molecular taxonomy could help facilitate precision oncology.
基金supported by Nanjing Plastech Pharmaceutical Technology Co.,Ltd.the Talent Project for Suzhou Municipal Health Commission(GSWS2021037).
文摘Dear Editor,Recent advancements in cancer drug discovery have shifted focus toward targeting the intrinsic properties of tumor cells,such as lineage plasticity and epigenetic regulation(Hanahan,2022;Yuan et al.,2019).This approach aims to induce re-differentiation or reprogramming of dedifferentiated cells,offering significant clinical potential for improving cancer treatment outcomes(Gong et al.,2019).
基金supported in part by the Canadian Institutes of Health Research(#173338,#180554,#186331)Terry Fox Research Institute(#1109),A PNW Prostate Cancer SPORE(P50 CA097186)pilot grant+1 种基金a Canadian Cancer Society Breakthrough Team Grant generously supported by the Lotte&John Hecht Memorial Foundation(CCS grant#707683)the BC Cancer Foundation(grant#1PRRG012).
文摘Treatment-induced neuroendocrine prostate cancer(NEPC)represents a lethal evolution of prostate adenocarcinoma under androgen receptor pathway inhibition,posing a significant clinical challenge.In a recent landmark study,Wang et al.introduced an innovative internal Z-score based approach to comprehensively characterize the transcription factor(TF)landscape in prostate cancer progression,uncovering distinct TF profiles associated with adenocarcinoma and NEPC lineages.Notably,the study proposes a three-phase model of NEPC transdifferentiation-comprising de-differentiation,dormancy,and re-differentiation-revealing dynamic shifts in TF expression that underpin lineage plasticity and therapeutic resistance.This commentary critically evaluates the methodological advancements,the functional significance of the identified TF signatures,and the broader implications of these findings for developing novel therapeutic strategies.By delineating the molecular events driving the transition from androgen receptor(AR)-dependent adenocarcinoma to treatment-resistant NEPC,this work underscores the potential of targeting early and dormant phases of transdifferentiation to improve patient outcomes.
基金supported by National Natural Science Foundation of China(No.81860524)Zunyi Municipal Bureau of Industry,Science and Technology[Zun shi ke he HZ zi(2024)No.216]。
文摘Prostate cancer remains a major health problem,with its incidence ranking second among male malignancies worldwide.Recent studies have highlighted the critical role of the SOX family transcription factors,especially SOX2,in prostate cancer pathogenesis.SOX2 regulates the fate of cancer stem/progenitor cells,contributing to tumor initiation,development,and metastasis.Elevated SOX2 levels have been detected in prostate cancer tissues and are associated with higher tumor grade,aggressive phenotype,and poor prognosis.SOX2 also impacts various tumor biological behaviors,including cell proliferation,invasion,metastasis,resistance to apoptosis,and treatment resistance.This review highlights the role of SOX proteins in prostate cancer,focusing on the molecular mechanisms by which SOX2 drives cancer progression,elucidating the mechanisms controlling its activity,and emphasizing its potential as a therapeutic target.
基金Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant numbers CA97098,CA166480 and CA233084 awarded to D.Kufe。
文摘The mucin 1(MUC1)gene emerged in mammals to afford protection of barrier epithelial tissues from the external environment.MUC1 encodes a transmembrane C-terminal(MUC1-C)subunit that is activated by loss of homeostasis and induces inflammatory,proliferative,and remodeling pathways associated with wound repair.As a consequence,chronic activation of MUC1-C promotes lineage plasticity,epigenetic reprogramming,and carcinogenesis.In driving cancer progression,MUC1-C is imported into the nucleus,where it induces NF-κB inflammatory signaling and the epithelial-mesenchymal transition(EMT).MUC1-C represses gene expression by activating(i)DNA methyltransferase 1(DNMT1)and DNMT3b,(ii)Polycomb Repressive Complex 1(PRC1)and PRC2,and(iii)the nucleosome remodeling and deacetylase(NuRD)complex.PRC1/2-mediated gene repression is counteracted by the SWI/SNF chromatin remodeling complexes.MUC1-C activates the SWI/SNF BAF and PBAF complexes in cancer stem cell(CSC)models with the induction of genome-wide differentially accessible regions and expressed genes.MUC1-C regulates chromatin accessibility of enhancer-like signatures in association with the induction of the Yamanaka pluripotency factors and recruitment of JUN and BAF,which promote increases in histone activation marks and opening of chromatin.These and other findings described in this review have uncovered a pivotal role for MUC1-C in integrating lineage plasticity and epigenetic reprogramming,which are transient in wound repair and sustained in promoting CSC progression.
文摘Treatment-induced neuroendocrine prostate cancer(t-NEPC)is a lethal subtype of castration-resistant prostate cancer(CRPC)characterized by unique pathological features and molecular changes,including the loss of an-drogen receptor(AR)activities and the gain of neuroendocrine gene expression.The incidence of t-NEPC has increased substantially in the last decade,in up to 20%of CRPC cases,largely due to intensive treatment of advanced prostate cancer(PCa)with AR pathway inhibitors(ARPi).While genomic alterations between CRPC and t-NEPC are largely conserved,their epigenetic programs are markedly distinct.The molecular mechanisms underlying the neuroendocrine transformation(NET)of PCa are rapidly emerging.Here,we first briefly summa-rize the genetic drivers of t-NEPC and then comprehensively review 2D and 3D chromatin alterations,including changes in DNA methylation,histone modifications,chromatin accessibility,and 3D chromatin organization,during NET of PCa.We then review key molecular regulators,including lineage-specific transcription factors and chromatin modifiers,of such epigenetic programs.Lastly,we discuss evidence that suggests a mixed model of clonal selection and transformation that underlies NEPC progression.
