The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only...The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.展开更多
Poor differentiation is an important hallnnark of cancer cells,and differentiation therapy holds great promise for cancer treatment.The restoration of IkB kinase a(IKKa)leads to the differentiation of nasopharyngeal c...Poor differentiation is an important hallnnark of cancer cells,and differentiation therapy holds great promise for cancer treatment.The restoration of IkB kinase a(IKKa)leads to the differentiation of nasopharyngeal carcinoma cells with reduced tumorigenicity.The findings by Yan et al.validate the polycomb protein enhancer of zeste homologue2(EZH2)as a target for intervention.展开更多
Psychological stress causes gut microbial dysbiosis and cancer progression,yet how gut microbiota determines psychological stressinduced tumor development remains unclear.Here we showed that psychological stress promo...Psychological stress causes gut microbial dysbiosis and cancer progression,yet how gut microbiota determines psychological stressinduced tumor development remains unclear.Here we showed that psychological stress promotes breast tumor growth and cancer stemness,an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice.Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota,especially Akkermansia muciniphila(A.muciniphila),and decreases short-chain fatty acid butyrate.Supplement of active A.muciniphila,butyrate or a butyrateproducing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model.Mechanistically,RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway,dampening breast cancer stemness.Moreover,butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36,which further accelerates LRP5 mRNA decay by binding adenine uridine-rich(AU-rich)elements of LRP5 transcript.Clinically,fecal A.muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression,poor prognosis and negative mood in breast cancer patients.Altogether,our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness,and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.展开更多
Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types.Tumor-associated macrophages(TAMs)play a key role in promoting tumor malignant progression and therapy resistance...Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types.Tumor-associated macrophages(TAMs)play a key role in promoting tumor malignant progression and therapy resistance.However,the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic.This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo.TAMs have been found to suppress cervical cancer cells ferroptosis.Mechanistically,macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells.In cancer cells,miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis.Moreover,the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway.Importantly,in clinical cervical cancer cases,ALOX15 is negatively associated with macrophages infiltration,which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer.Moreover,both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer.Altogether,this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.展开更多
Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology,and immune checkpoint inhibitors have successfully achieved responses in numbe...Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology,and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types,including hematopoietic malignancy.However,acute myeloid leukemia(AML)is a heterogeneous disease and there is stll a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage.展开更多
Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation o...Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m^(6)A reader YTHDC1 in lung cancer.Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing,specifically triggering RBM4 splicing from the full isoform(RBM4-FL)to the short isoform(RBM4-S)in a kinase-independent manner.展开更多
Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression.However,targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail.Here,we ...Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression.However,targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail.Here,we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis(ETBF)was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy.ETBF,albeit at low biomass,secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance.Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein.NOD1 was highly expressed on ALDH+breast cancer stem cells(BCSCs)and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation,thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs.NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.展开更多
Alternative splicing is a critical process to generate protein diversity.However,whether and how alternative splicing regulates autophagy remains largely elusive.Here we systematically identify the splicing factor SRS...Alternative splicing is a critical process to generate protein diversity.However,whether and how alternative splicing regulates autophagy remains largely elusive.Here we systematically identify the splicing factor SRSF1 as an autophagy suppressor.Specifically,SRSF1 inhibits autophagosome formation by reducing the accumulation of LC3-ⅡI and numbers of autophagosomes in different cell lines.Mechanistically,SRSF1 promotes the splicing of the long isoform of Bcl-x that interacts with Beclinl,thereby dissociating the Beclin1-PIK3C3 complex.In addition,SRSF1 also directly interacts with PIK3C3 to disrupt the interaction between Beclinl and PIK3C3.Consequently,the decrease of SRSF1 stabilizes the Beclinl and PIK3C3 complex and activates autophagy.Interestingly,SRSF1 can be degraded by starvation-and oxidative stresses-induced autophagy through interacting with LC3-Ⅱ,whereas reduced SRSF1 further promotes autophagy.This positive feedback is critical to inhibiting Gefitinib-resistant cancer cell progression both in vitro and in vivo.Consistently,the expression level of SRSF1 is inversely correlated to LC3 level in clinical cancer samples.Our study not only provides mechanistic insights of alternative splicing in autophagy regulation but also discovers a new regulatory role of SRSF1 in tumorigenesis,thereby offering a novel avenue for potential cancer therapeutics.展开更多
Background:Increasing studies have reported that oncogenes regulate components of the immune system,suggesting that this is a mechanism for tumorigenesis.Aurora kinase A(AURKA),a serine/threonine kinase,is involved in...Background:Increasing studies have reported that oncogenes regulate components of the immune system,suggesting that this is a mechanism for tumorigenesis.Aurora kinase A(AURKA),a serine/threonine kinase,is involved in cell mitosis and is essential for tumor cell proliferation,metastasis,and drug resistance.However,the mechanism by which AURKA is involved in immune response regulation is unclear.Therefore,this study aimed to investigate the role of AURKA in immune regulation in triple-negative breast cancer(TNBC).Methods:Peripheral blood mononuclear cells(PBMCs)were co-cultured with TNBC cells.The xCELLigence Real-Time Cell Analyzer-MP system was used to detect the killing efficiency of immune cells on TNBC cells.The expression of immune effector molecules was tested by quantitative real-time polymerase chain reaction(qRT-PCR)to evaluate immune function.Furthermore,to validate AURKA-regulated immune response in vivo,4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice.The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry.Results:Downregulation of AURKA in TNBC cells increased immune response by activating CD8^(+)T cell proliferation and activity.Nuclear rather than cytoplasmic AURKA-derived programmed death-ligand 1(PD-L1)expression was independent of its kinase activity.Mechanistic investigations showed that nuclear AURKA increased PD-L1 expression via an MYC-dependent pathway.PD-L1 overexpression mostly reversed AURKA silencing-induced expression of immune effector molecules,including interleukin-(IL-2),interferon-γ(IFN-γ),and perforin.Moreover,AURKA expression was negatively correlated with the enrichment and activity of tumor-infiltrating CD8^(+)T cells in 4T1 engrafted BALB/c mouse model.Conclusions:Nuclear AURKA elevated PD-L1 expression via an MYCdependent pathway and contributed to immune evasion in TNBC.Therapies targeting nuclear AURKA may restore immune responses against tumors.展开更多
Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high ...Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)infection.Here,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA.Mechanistically,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone acetylation.HDAC inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft models.These fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.展开更多
Background:Overexpression of Aurora-A(AURKA)is a feature of breast cancer and associates with adverse prognosis.The selective Aurora-A inhibitor alisertib(MLN8237)has recently demonstrated promising antitumor response...Background:Overexpression of Aurora-A(AURKA)is a feature of breast cancer and associates with adverse prognosis.The selective Aurora-A inhibitor alisertib(MLN8237)has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of patients.Thus,identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic outcome.Methods:Here,we conducted a systematic synthetic lethality CRISPR/Cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with MLN8237.Then,we performed competitive growth assays,colony formation assays,cell viability assays,apoptosis assays,and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin(GSG2)depletion or inhibition with MLN8237.For mechanistic studies,immunofluorescence was used to detect the state of microtubules and the localization of Aurora-B and mitotic centromere-associated kinesin(MCAK).Results:Among the hits,we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of MLN8237.Mechanistic studies showed that co-treatment with Aurora-A and Haspin inhibitors abolished the recruitment of Aurora-B and mitotic centromere-associated kinesin(MCAK)to centromeres which were associated with excessive microtubule depolymerization,kinetochore-microtubule(KT-MT)attachment failure,and severe mitotic catastrophe.We further showed that the combination of MLN8237 and the Haspin inhibitor CHR-6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor growth.Conclusions:These findings establish Haspin as a synthetic lethal target and demonstrate CHR-6494 as a potential combinational drug for promoting the therapeutic effects of MLN8237 on breast cancer.展开更多
Cancer cell receives extracellular signal inputs to obtain a stem-like status,yet how tumor microenvironmental(TME)neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive...Cancer cell receives extracellular signal inputs to obtain a stem-like status,yet how tumor microenvironmental(TME)neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive.Here,a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element(CRE)transcription factors are convergent activators for cancer stemness.Deconvolution of transcriptomic profiles,specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity.Specifically,neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis,where ATF1 serves as a conserved hub.Upon activation by norepinephrine,ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM,thereby orchestrating nuclear reprograming and mitochondrial rejuvenating.Accordingly,single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells.These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program,suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.展开更多
Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strat...Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions,but also provide an avenue for precision medicine.Here,we explore the current approaches for targeting intratumor hetero-geneity and their limitations.Furthermore,we propose a theoretical strategy with a“homogenization”feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.展开更多
During mitosis,the allocation of genetic material concurs with organelle transformation and distribution.The coordination of genetic material inheritance with organelle dynamics directs accurate mitotic progression,ce...During mitosis,the allocation of genetic material concurs with organelle transformation and distribution.The coordination of genetic material inheritance with organelle dynamics directs accurate mitotic progression,cell fate determination,and organismal homeostasis.Small GTPases belonging to the Ras superfamily regulate various cell organelles during division.Being the key regulators of membrane dynamics,the dysregulation of small GTPases is widely associated with cell organelle disruption in neoplastic and non-neoplastic diseases,such as cancer and Alzheimer’s disease.Recent discoveries shed light on the molecular properties of small GTPases as sophisticated modulators of a remarkably complex and perfect adaptors for rapid structure reformation.This review collects current knowledge on small GTPases in the regulation of cell organelles during mitosis and highlights the mediator role of small GTPase in transducing cell cycle signaling to organelle dynamics during mitosis.展开更多
Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoverie...Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoveries have been made on BCSC characterization,the factors critical to the origination of BCSCs are largely unclear.This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs.Methods:We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency,and then performed target deep DNA sequencing at bulk-cell and single-cell levels.To identify the transcriptional program associated with BCSCs,bulk-cell and single-cell RNA sequencing was performed.Results:By using whole-genome sequencing of bulk cells,potential BCSC phenotype-associated mutation hotspot regions were detected.Validation by target deep DNA sequencing,at both bulk-cell and single-cell levels,revealed no genetic changes specifically associated with BCSC phenotype.Moreover,single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features.Notably,this transcriptomic variability was enriched during the transcription of 74 genes,revealed as BCSC markers.Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse,thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers.Conclusions:Transcriptomic variability,not genetic mutations,distinguishes BCSCs from non-BCSCs.The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.展开更多
Introduction Cancer heterogeneity has been characterized with distinct differentiation states,metabolic status,and microenvironmental features,accounting for diverse responses to therapy.Recent view has proposed 14 ha...Introduction Cancer heterogeneity has been characterized with distinct differentiation states,metabolic status,and microenvironmental features,accounting for diverse responses to therapy.Recent view has proposed 14 hallmarks of cancer in order to provide a logical framework for the comprehensive understanding of the characteristics and processes responsible for malignant transformation and progression[1,2].展开更多
基金supported by the China Central Budget Recruitment Program of High?Level Overseas Talent (GDW 201221022066 to Q.Liu)the National Basic Research Program of China (973 Program:No.2012CB967000 to Q.Liu)+2 种基金the National Natural Science Foundation of China (NNSF No.81130040 to Q.Liu and No.81201686 to J.Xu)the Program for Changjiang Scholars and Innovative Research Team in Universities (ITR 13049 to Q.Liu)the Liaoning (NSF 2014029102 to Q.Liu)
文摘The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.
基金the National Basic Research Program of China(973 Program,No.2012CB967000 and 2011CB504300 to QL)Program for Chang Jiang Scholars and Innovative Research Team in University(IRTI 3049 to QL)+1 种基金National Natural Science Foundation of China(No.30888003 to QL and No.81201547 to MY)Guangdong Medical Science Fund(A2011198 to MY)
文摘Poor differentiation is an important hallnnark of cancer cells,and differentiation therapy holds great promise for cancer treatment.The restoration of IkB kinase a(IKKa)leads to the differentiation of nasopharyngeal carcinoma cells with reduced tumorigenicity.The findings by Yan et al.validate the polycomb protein enhancer of zeste homologue2(EZH2)as a target for intervention.
基金supported by the Science Fund for Creative Research Groups of the National Natural Science Foundation of China(82321003)the National Natural Science Foundation of China(82273480,82341020,82473131,82373096,82173361)+4 种基金National Key R&D Program of China(2022YFA1104002)Applied Basic Research Planning Project of Liaoning(2023JH2/101600019)Science and technology innovation team project of basic scientific research project of Liaoning Provincial Department of Education(LJ222410161065)the Science and Technology Talent Innovation Support Policy Implementation Program of Dalian-Outstanding young scientific and technological talents(2023RY013)the Shenzhen Bay Laboratory ResearchFunds(SZBL2021080601001toQL).
文摘Psychological stress causes gut microbial dysbiosis and cancer progression,yet how gut microbiota determines psychological stressinduced tumor development remains unclear.Here we showed that psychological stress promotes breast tumor growth and cancer stemness,an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice.Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota,especially Akkermansia muciniphila(A.muciniphila),and decreases short-chain fatty acid butyrate.Supplement of active A.muciniphila,butyrate or a butyrateproducing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model.Mechanistically,RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway,dampening breast cancer stemness.Moreover,butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36,which further accelerates LRP5 mRNA decay by binding adenine uridine-rich(AU-rich)elements of LRP5 transcript.Clinically,fecal A.muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression,poor prognosis and negative mood in breast cancer patients.Altogether,our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness,and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.
基金supported by the National Natural Science Foundation of China(81972479,U2004118,82072899,81772643 and 81772803)Natural Science Foundation of Guangdong province(2019A1515011100 and 2021A1515012576,China)+5 种基金Henan Natural Science Foundation(202300410359,China)Henan Medical Program(SBGJ2020002081,China)Guangzhou High-Level Clinical Key Specialty Construction ProjectClinical Key Specialty Construction Project of Guangzhou Medical University(202005,China)the Innovation Project of Universities in Guangdong Province(NO.2021KTSCX026,China)Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University(QNCXTD2023019,China)。
文摘Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types.Tumor-associated macrophages(TAMs)play a key role in promoting tumor malignant progression and therapy resistance.However,the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic.This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo.TAMs have been found to suppress cervical cancer cells ferroptosis.Mechanistically,macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells.In cancer cells,miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis.Moreover,the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway.Importantly,in clinical cervical cancer cases,ALOX15 is negatively associated with macrophages infiltration,which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer.Moreover,both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer.Altogether,this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.
基金This study was supported by Training Project for National Natural Science Foundation from The Third Affliated Hospital of Sun Yat-sen University(No.2022GZRPYMS05 to Zi-Jie Long)Science and Technology Planning Project of Guangzhou(No.202201020400 to Zi-Jie Long).
文摘Immunotherapy is a revolutionized therapeutic strategy for tumor treatment attributing to the rapid development of genomics and immunology,and immune checkpoint inhibitors have successfully achieved responses in numbers of tumor types,including hematopoietic malignancy.However,acute myeloid leukemia(AML)is a heterogeneous disease and there is stll a lack of systematic demonstration to apply immunotherapy in AML based on PD-1/PD-L1 blockage.
基金We thank Quentin Liu’s lab members for their critical comments and technical support.We thank Eric W.-F.Lam for his critical reading of the manuscript and insightful suggestions.This research work was supported by the National Natural Science Foundation of China(No.81820108024 to Q.L.,No.81630005 to Q.L.,No.81830088 to Y.W.,No.81873441 to B.-L.J.,No.82103659 to S.-S.L.,No.8210113819 to Y.-F.Q.,No.81972786 to J.X.,No.82003141 to F.P.,No.82002960 to B.C.,No.31801100 to X.-.D.D.)National Key R&D Program of China(2019YFA0110300 to Q.L.and 2017YFA0505600-04 to Q.L.)+12 种基金Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)Innovative Research Team in University of Liaoning(No.LT2017001 to Q.L.)Heilongjiang Postdoctoral Fund(No.LBH-Z20074 to S.-S.L.)Harbin Medical University Doctor Green Seedling Ground-breaking Project(No.QMPT-1909 to S.-S.L.)the Natural Science Foundation of Liaoning(No.2019-BS-081 to F.P.)the“Seedling cultivation”program for young scientific and technological talents of Liaoning(No.LZ2020044 to F.P.,No.LZ2019067 to B.C.)Dalian Science and Technology program-The central government guiding local funding projects for scientific and technological development(2021 to F.P.)Dalian High-level Talents Innovation Support Program-Young Science and Technology Star(2021RQ004 to B.C.)the program for climbing Scholars of Liaoning,the Science and Technology Innovation Foundation of Dalian(No.2020JJ25CY008 to Q.L.)International Scientific and Technological Cooperation of Dalian(2015F11GH095 to Q.L.)the Natural Science Foundation of Guangdong(2016A030311038 and 2017A030313608 to Q.L.)the Science and Technology Planning Project of Guangzhou(No.201804020044 to Q.L.)the Scientific Research Project of Guangzhou(No.201904010492 to B.-L.J.).
文摘Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression,yet how this process is regulated by oncogenic signal remains largely unknown.Here,we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m^(6)A reader YTHDC1 in lung cancer.Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing,specifically triggering RBM4 splicing from the full isoform(RBM4-FL)to the short isoform(RBM4-S)in a kinase-independent manner.
基金supported by National Key Research and Development Program of China(2023YFC2506400,2020YFA0112300)National Natural Science Foundation of China(Grant Nos.82230103,81930075,82073267,82203399,82072903)+7 种基金“Ten Thousand Plan”—National High-Level Talents Special Support Plan WR-YK5202101Program of Shanghai Academic/Technology Research Leader 20XD1400700Program for Outstanding Medical Academic Leader in Shanghai(2019LJ04)The innovative research team of high-level local university in ShanghaiThe Fudan University Research Foundation(IDH 1340042)The Research Foundation of the Fudan University Shanghai Cancer Center(YJRC1603)Shanghai Anticancer Association EYAS PROJECT(SACA-CY23B07)The Natural Science Foundation of Hunan Province(2020JJ4916).
文摘Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression.However,targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail.Here,we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis(ETBF)was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy.ETBF,albeit at low biomass,secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance.Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein.NOD1 was highly expressed on ALDH+breast cancer stem cells(BCSCs)and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation,thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs.NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.
基金This work was supported by the National Natural Science Foundation of China(81830088,81422038,91540110,and 31471235 to Y.W.,81872247 and 31400726 to W.Z.)the Department of Education of Liaoning Province(the"Liaoning Supports High Level Talents Innovation and Entrepreneurship Program"XLYC1802067 to Y.W.)+1 种基金the Department of Science and Technology of Dalian City(the HDalian Supports High Level Talents Innovation and Entrepreneurship Program" 2016RJ02 to Y.W.)the Newton Advanced Fellowship from the Academy of Medical Sciences in UK(JXR11831 to Y.W.).
文摘Alternative splicing is a critical process to generate protein diversity.However,whether and how alternative splicing regulates autophagy remains largely elusive.Here we systematically identify the splicing factor SRSF1 as an autophagy suppressor.Specifically,SRSF1 inhibits autophagosome formation by reducing the accumulation of LC3-ⅡI and numbers of autophagosomes in different cell lines.Mechanistically,SRSF1 promotes the splicing of the long isoform of Bcl-x that interacts with Beclinl,thereby dissociating the Beclin1-PIK3C3 complex.In addition,SRSF1 also directly interacts with PIK3C3 to disrupt the interaction between Beclinl and PIK3C3.Consequently,the decrease of SRSF1 stabilizes the Beclinl and PIK3C3 complex and activates autophagy.Interestingly,SRSF1 can be degraded by starvation-and oxidative stresses-induced autophagy through interacting with LC3-Ⅱ,whereas reduced SRSF1 further promotes autophagy.This positive feedback is critical to inhibiting Gefitinib-resistant cancer cell progression both in vitro and in vivo.Consistently,the expression level of SRSF1 is inversely correlated to LC3 level in clinical cancer samples.Our study not only provides mechanistic insights of alternative splicing in autophagy regulation but also discovers a new regulatory role of SRSF1 in tumorigenesis,thereby offering a novel avenue for potential cancer therapeutics.
基金National Natural Science Foundation of China,Grant/Award Numbers:81702621,81630005,81820108024,81972594,82003141,82002960,31801100,81703062National Key Research and Development Program,Grant/Award Number:2016YFC1303001+2 种基金Natural Science Foundation of Liaoning Province,Grant/Award Numbers:20180550618,2019-BS-081Guangdong Basic and Applied Basic Research Foundation,Grant/Award Numbers:2018A0303130299,2020A1515010608“Seedling cultivation”programfor young scientific and technological talents of Liaoning,Grant/Award Numbers:LZ2020044,LZ2019067。
文摘Background:Increasing studies have reported that oncogenes regulate components of the immune system,suggesting that this is a mechanism for tumorigenesis.Aurora kinase A(AURKA),a serine/threonine kinase,is involved in cell mitosis and is essential for tumor cell proliferation,metastasis,and drug resistance.However,the mechanism by which AURKA is involved in immune response regulation is unclear.Therefore,this study aimed to investigate the role of AURKA in immune regulation in triple-negative breast cancer(TNBC).Methods:Peripheral blood mononuclear cells(PBMCs)were co-cultured with TNBC cells.The xCELLigence Real-Time Cell Analyzer-MP system was used to detect the killing efficiency of immune cells on TNBC cells.The expression of immune effector molecules was tested by quantitative real-time polymerase chain reaction(qRT-PCR)to evaluate immune function.Furthermore,to validate AURKA-regulated immune response in vivo,4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice.The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry.Results:Downregulation of AURKA in TNBC cells increased immune response by activating CD8^(+)T cell proliferation and activity.Nuclear rather than cytoplasmic AURKA-derived programmed death-ligand 1(PD-L1)expression was independent of its kinase activity.Mechanistic investigations showed that nuclear AURKA increased PD-L1 expression via an MYC-dependent pathway.PD-L1 overexpression mostly reversed AURKA silencing-induced expression of immune effector molecules,including interleukin-(IL-2),interferon-γ(IFN-γ),and perforin.Moreover,AURKA expression was negatively correlated with the enrichment and activity of tumor-infiltrating CD8^(+)T cells in 4T1 engrafted BALB/c mouse model.Conclusions:Nuclear AURKA elevated PD-L1 expression via an MYCdependent pathway and contributed to immune evasion in TNBC.Therapies targeting nuclear AURKA may restore immune responses against tumors.
基金supported by National Key R&D Program of China(2019YFA0110300,2017YFA0505600-04 to Q.L.)Innovative Research Team in University of Ministry of Education of China(IRT_17R15 to Q.L.)+7 种基金National Natural Science Foundation of China(81630005,81573025 to Q.L.,81773166 to Z.W.,81702683 to J.X.,81972594 to M.Y.,81402445 to C.W.,81502579 to Z.H.)Natural Science Foundation of Guangdong(2017A030313608 to Q.L,2018A0303130299,2020A1515010608 to M.Y.)the Science and Technology Planning Project of Guangzhou(201804020044 to Q.L.)the Key Project of Liaoning Natural Science Funding of China(201702031 to Q.L.)Fundamental Research Funds for the Central Universities(I9ykpy187 to M.Y.).EW-FL's work is supported by MRC(MR/N012097/1)CRUK(Al 2011)Breast Cancer Now(2012MayPR070,2012NovPhD016)the Cancer Research UK Imperial Centre,Imperial ECMC,and NIHR Imperial BRC.
文摘Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging.Nasopharyngeal carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)infection.Here,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA.Mechanistically,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone acetylation.HDAC inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft models.These fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.
基金This research work was supported by the National Key R&D Program of China(2019YFA0110300 and 2017YFA0505600-04 to QL)the National Natural Science Foundation of China(81820108024 and 81630005 to QL,81773166 to ZFW)+2 种基金the Innovative Research Team at the University of Ministry of Education of China(IRT-17R15 to QL)the Natural Science Foundation of Guangdong(2016A030311038 and 2017A030313608 to QL,2017A020215098 to ZFW)the Science and Technology Planning Project of Guangzhou(201804020044 to QL).
文摘Background:Overexpression of Aurora-A(AURKA)is a feature of breast cancer and associates with adverse prognosis.The selective Aurora-A inhibitor alisertib(MLN8237)has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of patients.Thus,identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic outcome.Methods:Here,we conducted a systematic synthetic lethality CRISPR/Cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with MLN8237.Then,we performed competitive growth assays,colony formation assays,cell viability assays,apoptosis assays,and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin(GSG2)depletion or inhibition with MLN8237.For mechanistic studies,immunofluorescence was used to detect the state of microtubules and the localization of Aurora-B and mitotic centromere-associated kinesin(MCAK).Results:Among the hits,we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of MLN8237.Mechanistic studies showed that co-treatment with Aurora-A and Haspin inhibitors abolished the recruitment of Aurora-B and mitotic centromere-associated kinesin(MCAK)to centromeres which were associated with excessive microtubule depolymerization,kinetochore-microtubule(KT-MT)attachment failure,and severe mitotic catastrophe.We further showed that the combination of MLN8237 and the Haspin inhibitor CHR-6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor growth.Conclusions:These findings establish Haspin as a synthetic lethal target and demonstrate CHR-6494 as a potential combinational drug for promoting the therapeutic effects of MLN8237 on breast cancer.
基金This research work was supported by the National Key R&D Program of China(2019YFA0110300 to Q.L.)the National Natural Science Foundation of China(No.82003096 to R.G.,No.82002943 to B.H.,No.81820108024 to Q.L.and No.81972594 to M.Y.)+1 种基金the Natural Science Foundation of Guangdong(2017A030313608 to Q.L.)the Science and Technology Planning Project of Guangzhou(201804020044 to Q.L.).
文摘Cancer cell receives extracellular signal inputs to obtain a stem-like status,yet how tumor microenvironmental(TME)neural signals steer cancer stemness to establish the hierarchical tumor architectures remains elusive.Here,a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element(CRE)transcription factors are convergent activators for cancer stemness.Deconvolution of transcriptomic profiles,specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE activity.Specifically,neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis,where ATF1 serves as a conserved hub.Upon activation by norepinephrine,ATF1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRF1/TFAM,thereby orchestrating nuclear reprograming and mitochondrial rejuvenating.Accordingly,single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like cells.These findings elucidate that cancer cell acquires stemness via a norepinephrine-ATF1 driven nucleus-mitochondria collaborated program,suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.
基金supported by Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)National Natural Science Foundation of China(No.81630005 to QL,No.81573025 to QL)+1 种基金Dalian high-level talent innovation program(2016RD12 to QL)International scientific and technological cooperation of Dalian(2015F11GH095 to QL).
文摘Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions,but also provide an avenue for precision medicine.Here,we explore the current approaches for targeting intratumor hetero-geneity and their limitations.Furthermore,we propose a theoretical strategy with a“homogenization”feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.
基金supported by the National Kcy R&D Program of China(Nos.2019YFA0110300 and 2017YFA0505600-04)the National Natural Science Foundation of China(Nos.81820108024 and 81630005)+1 种基金the Innovative Research Team in University of Ministry of Edueation of China(No.IRT-17R15)and the Natural Science Foundation of Guangdong(Nos.2016A030311038 and 2017A030313608).
文摘During mitosis,the allocation of genetic material concurs with organelle transformation and distribution.The coordination of genetic material inheritance with organelle dynamics directs accurate mitotic progression,cell fate determination,and organismal homeostasis.Small GTPases belonging to the Ras superfamily regulate various cell organelles during division.Being the key regulators of membrane dynamics,the dysregulation of small GTPases is widely associated with cell organelle disruption in neoplastic and non-neoplastic diseases,such as cancer and Alzheimer’s disease.Recent discoveries shed light on the molecular properties of small GTPases as sophisticated modulators of a remarkably complex and perfect adaptors for rapid structure reformation.This review collects current knowledge on small GTPases in the regulation of cell organelles during mitosis and highlights the mediator role of small GTPase in transducing cell cycle signaling to organelle dynamics during mitosis.
基金supported by Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China(No.IRT_17R15)National Natural Science Foundation of China(Nos.81630005 to QL,81573025 to QL,81472637 to ZL,81672784 to ZL,and 81602200 to DL)+2 种基金Innovative Research Team in University of Liaoning(No.LT2017001 to QL)The program for climbing Scholars of Liaoning,Dalian High-level Talent Innovation Program(2016RD12 to QL)International Scientific and Technological Cooperation of Dalian(2015F11GH095 to QL).
文摘Background:Breast cancer stem cells(BCSCs)are considered responsible for cancer relapse and drug resistance.Understanding the identity of BCSCs may open new avenues in breast cancer therapy.Although several discoveries have been made on BCSC characterization,the factors critical to the origination of BCSCs are largely unclear.This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs.Methods:We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency,and then performed target deep DNA sequencing at bulk-cell and single-cell levels.To identify the transcriptional program associated with BCSCs,bulk-cell and single-cell RNA sequencing was performed.Results:By using whole-genome sequencing of bulk cells,potential BCSC phenotype-associated mutation hotspot regions were detected.Validation by target deep DNA sequencing,at both bulk-cell and single-cell levels,revealed no genetic changes specifically associated with BCSC phenotype.Moreover,single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features.Notably,this transcriptomic variability was enriched during the transcription of 74 genes,revealed as BCSC markers.Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse,thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers.Conclusions:Transcriptomic variability,not genetic mutations,distinguishes BCSCs from non-BCSCs.The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.
基金supported by the National Key Research and Development Program of China(No.2019YFA0110303 to Quentin Liu)the National Natural Science Foundation of China(No.81972594 to Min Yan)+1 种基金the Innovative Research Team in University of Ministry of Education of China(No.IRT-17R15 to Quentin Liu)the Natural Science Foundation of Guangdong(No.2020A1515010608 to Min Yan).
文摘Introduction Cancer heterogeneity has been characterized with distinct differentiation states,metabolic status,and microenvironmental features,accounting for diverse responses to therapy.Recent view has proposed 14 hallmarks of cancer in order to provide a logical framework for the comprehensive understanding of the characteristics and processes responsible for malignant transformation and progression[1,2].
