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Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1

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Protein & Cell 2024年第6期15卷 419-440页

作者： Wei Ma Lu Zhang Weilong Chen Zhaoxia Chang Juchuanli Tu Yuanyuan Qin Yuwen Yao Mengxue Dong Jiajun Ding Siqin Li Fengkai Li Qiaodan Deng Yifei Yang Tingting Feng Fanrong Zhang Xiying Shao Xueyan He Lixing Zhang Guohong Hu quentin liu Yi-Zhou Jiang Shu Zhu Zhi Xiao Dan Su Tong liu Suling liu Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences State Key Laboratory of Genetic EngineeringCancer InstitutesDepartment of OncologyKey Laboratory of Breast Cancer in ShanghaiThe Shanghai Key Laboratory of Medical EpigeneticsShanghai Key Laboratory of Radiation OncologyThe International Co-laboratory of Medical Epigenetics and MetabolismMinistry of Science and TechnologyShanghai Medical CollegeFudan UniversityShanghai 200032China Intelligent Pathology Institute and Department of Pathology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230071China Department of Thyroid Breast and Vascular SurgeryXijing HospitalFourth Military Medical UniversityXi’an 710032China Institute of Immunology CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Basic Medical SciencesDivision of Life Science and MedicineUniversity of Science and Technology of ChinaHefei 230027China Department of Pathology The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhou 310022China Department of Breast Surgery The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhou 310022China Department of Breast Medical Oncology The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital)Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhou 310022China Shanghai Institute of Nutrition and Health University of Chinese Academy of SciencesChinese Academy of SciencesShanghai 200031China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaGuangzhou 510060China Department of Breast Surgery Xiangya HospitalChangsha 410008China Department of Breast Surgery Tumor Hospital of Harbin Medic

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.

关键词： NOD1 breast chemotherapy

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Extended wet sieving method for determination of complete particle size distribution of general soils

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Journal of Rock Mechanics and Geotechnical Engineering 2024年第1期16卷 242-257页

作者： Shengnan Ma Yi Song Jiawei liu Xingyu Kang Zhongqi quentin Yue Department of Civil Engineering The University of Hong KongHong KongChina

The traditional standard wet sieving method uses steel sieves with aperture?0.063 mm and can only determine the particle size distribution(PSD)of gravel and sand in general soil.This paper extends the traditional method and presents an extended wet sieving method.The extended method uses both the steel sieves and the nylon filter cloth sieves.The apertures of the cloth sieves are smaller than 0.063 mm and equal 0.048 mm,0.038 mm,0.014 mm,0.012 mm,0.0063 mm,0.004 mm,0.003 mm,0.002 mm,and 0.001 mm,respectively.The extended method uses five steps to separate the general soil into many material sub-groups of gravel,sand,silt and clay with known particle size ranges.The complete PSD of the general soil is then calculated from the dry masses of the individual material sub-groups.The extended method is demonstrated with a general soil of completely decomposed granite(CDG)in Hong Kong,China.The silt and clay materials with different particle size ranges are further examined,checked and verified using stereomicroscopic observation,physical and chemical property tests.The results further confirm the correctness of the extended wet sieving method.

关键词： Particle size distribution(PSD) General soil Silt Clay Wet sieving Physical and chemical properties

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The nature of cancer

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Frontiers of Medicine 2023年第4期17卷 796-803页

作者： Min Yan quentin liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineGuangzhou 510060China Institute of Cancer Stem Cell Cancer CenterDalian Medical UniversityDalian 116023China

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].

关键词： cancer Cancer malignant

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Fine-tuning cell organelle dynamics during mitosis by small GTPases

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Frontiers of Medicine 2022年第3期16卷 339-357页

作者： Zijian Zhang Wei Zhang quentin liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China Department of Clinical Immunology The Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Institute of Cancer Stem Cell Dalian Medical UniversityDalian 116044China

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.

关键词： small GTPase cell organelle mitosis

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The suppression of cervical cancer ferroptosis by macrophages:The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes

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药学学报:英文版 2023年第6期13卷 2645-2662页

作者： Yanlin Luo Yibing Chen Huan Jin Benxin Hou Hongsheng Li Xiang Li Lingfeng liu Yuan Zhou Yonghua Li Yong Sang Song quentin liu Zhengzhi Zou Department of Gynecologic Oncology the Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhou 450001China MOE Key Laboratory of Laser Life Science&Institute of Laser Life Science Guangdong Provincial Key Laboratory of Laser Life ScienceCollege of BiophotonicsSouth China Normal UniversityGuangzhou 510631China Institute of Clinical Pharmacology School of Basic Medical ScienceAcademy of Medical ScienceZhengzhou UniversityZhengzhou 450001China Genetic and Prenatal Diagnosis Center Department of Gynecology and ObstetricsFirst Affiliated HospitalZhengzhou UniversityZhengzhou 450001China Department of General Surgery the Third People's Hospital of Hainan ProvinceSanya 572000China Department of Breast Surgery Affiliated Cancer Hospital&Institute of Guangzhou Medical UniversityGuangzhou 510095China Department of Pathophysiology School of Basic Medical SciencesZhengzhou UniversityZhengzhou 450001China Department of Obstetrics and Gynecology Cancer Research InstituteCollege of MedicineSeoul National UniversitySeoul 03080South Korea State Key Laboratory of Oncology in South China Cancer CenterSun Yat-sen UniversityGuangzhou 510631China Guangzhou Key Laboratory of Spectral Analysis and Functional Probes College of BiophotonicsSouth China Normal UniversityGuangzhou 510631China

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.

关键词： Cervical cancer Tumor-associated macrophage ALOX15 Ferroptosis Exosome miRNA-660-5p Macrophages infiltration STAT6

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Differentiation therapy:a promisingstrategy for cancer treatment

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Chinese Journal of Cancer 2016年第1期35卷 1-3页

作者： Min Yan quentin liu State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer Center510060 GuangzhouGuangdongP.R.China Institute of Cancer Stem Cell Cancer CenterDalian Medical University116044 DalianLiaoningP.R.China

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.

关键词： Differentiation therapy, Cancer treatment, IkB kinase α

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Cancer cell employs a microenvironmental neural signal transactivating nucleus-mitochondria coordination to acquire stemness

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Signal Transduction and Targeted Therapy 2023年第8期8卷 3818-3836页

作者： Bin He Rui Gao Shasha Lv Ailin Chen Junxiu Huang Luoxuan Wang Yunxiu Feng Jiesi Feng Bing liu Jie Lei Bing Deng Bin He Bai Cui Fei Peng Min Yan Zifeng Wang Eric W-F Lam Bilian Jin Zhiming Shao Yulong Li Jianwei Jiao Xi Wang quentin liu State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer CenterGuangzhou 510060PR China Department of Medical Oncology The Seventh Affiliated HospitalSun Yat-sen UniversityShenzhen 510275PR China Institute of Cancer Stem Cell Cancer CenterDalian Medical UniversityDalian 116023PR China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510080PR China State Key Laboratory of Membrane Biology Peking University School of Life SciencesBeijing 100871PR China Department of Surgery and Cancer Imperial College LondonLondon W120NNUK Department of Breast Surgery Precision Cancer Medicine CenterFudan University Shanghai Cancer CenterShanghai 200032PR China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101PR China

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.

关键词： Cancer neural architectures

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STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia

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Signal Transduction and Targeted Therapy 2023年第10期8卷 5106-5118页

作者： Ze-Wei Huang Xue-Ning Zhang Ling Zhang Ling-Ling liu Jing-Wen Zhang Yu-Xiang Sun Jue-Qiong Xu quentin liu Zi-Jie Long Department of Hematology The Third Affiliated HospitalSun Yat-sen UniversityInstitute of HematologySun Yat-sen UniversityGuangzhouChina Department of Nephrology The Third Affiliated Hospitalun Yat-sen UniversityGuangzhouChina Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaSun Yat-sen UniversityGuangzhouChina

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.

关键词： myeloid acute leukemia

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New insights from the widening homogeneity perspective to target intratumor heterogeneity

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Cancer Communications 2018年第1期38卷 195-201页

作者： Mengying Tong Ziqian Deng Xiaolong Zhang Bin He Mengying Yang Wei Cheng quentin liu Institute of Cancer Stem Cell Cancer CenterDalian Medical UniversityDalian 116044LiaoningP.R.China State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer CenterGuangzhou 510630GuangdongP.R.China Department of Hematology The Third Affiliated HospitalSun Yat-sen UniverisityGuangzhou 510630GuangdongP.R.China

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.

关键词： Acquired drug resistance Homogenization Intratumor heterogeneity Plasticity Precision medicine

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Nuclear Aurora kinase A triggers programmed death-ligand 1-mediated immune suppression by activating MYC transcription in triple-negative breast cancer

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Cancer Communications 2021年第9期41卷 851-866页

作者： Shulan Sun Wei Zhou Xiaoxi Li Fei Peng Min Yan Yajing Zhan Fan An Xiaoyan Li Yunyong liu quentin liu Haozhe Piao Central Laboratory Cancer Hospital of China Medical UniversityDalian Medical University Clinical Oncology CollegeLiaoning Cancer Hospital&InstituteShenyangLiaoning 110042P.R.China Institute of Cancer Stem Cell Dalian Medical UniversityDalianLiaoning 116044P.R.China State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer CenterGuangzhouGuangdong 510060P.R.China Department of Pathology Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital and instituteShenyangLiaoning 110042P.R.China Department of Cancer Prevention and Treatment Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital&InstituteShenyangLiaoning 110042P.R.China Department of Neurosurgery Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital&InstituteShenyangLiaoning 110042P.R.China

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.

关键词： Aurora kinase A immune evasion immunotherapy MYC programmed death-ligand 1 triplenegative breast cancer

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