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CD8+T cell metabolic flexibility elicited by CD28-ARS2 axisdriven alternative splicing of PKM supports antitumor immunity

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Cellular & Molecular Immunology 2024年第3期21卷 260-274页

作者： G.Aaron Holling Colin A.Chavel Anand P.Sharda Mackenzie M.Lieberman Caitlin M.James Shivana M.Lightman Jason H.Tong Guanxi Qiao Tiffany R.Emmons Thejaswini Giridharan Shengqi Hou Andrew M.Intlekofer Richard M.Higashi Teresa W.M.Fan Andrew N.Lane Kevin H.Eng Brahm H.Segal Elizabeth A.Repasky Kelvin P.Lee Scott H.Olejniczak department of Immunology Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA department of Medicine Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA center for Environmental Systems Biochemistry Department of Toxicology and Cancer Biology and Markey Cancer CenterLexingtonKY 40536USA department of cancer Genetics and Genomics Roswell Park Comprehensive Cancer CenterBuffaloNY 14263USA present address:University of Colorado Boulder BoulderCO 80309USA present address:Dana Farber cancer Institute BostonMA 02215USA present address:Massachusetts Institute of Technology BostonMA 02139USA present address:Melvin and Bren Simon Comprehensive cancer center Indiana University School of MedicineIndianapolisIN 46202USA

Metabolic flexibility has emerged as a critical determinant of CD8+T-cell antitumor activity,yet the mechanisms driving the metabolic flexibility of T cells have not been determined.In this study,we investigated the influence of the nuclear cap-binding complex(CBC)adaptor protein ARS2 on mature T cells.In doing so,we discovered a novel signaling axis that endows activated CD8+T cells with flexibility of glucose catabolism.ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events.Among these effects,the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2,a key determinant of CD8+T-cell glucose utilization,interferon gamma production,and antitumor effector function.Importantly,PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation,revealing a novel means by which costimulation reprograms glucose metabolism in CD8+T cells.

关键词： Immunometabolism mRNA splicing CD8 T cells ARS2 PKM2

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Modular Synthesis of Multi-substituted Cyclobutanones Enabled by Oxyallyl Cations

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Chinese Journal of Chemistry 2024年第5期42卷 459-463页

作者： Meng Wang Zhonggui Wang Ping Lu Research center for Molecular Recognition and Synthesis Department of ChemistryFudan University220 Handan LuShanghai200433 China present address: department of cancer Biology Dana-Farber Cancer Institute department of Biological Chemistry and Molecular Pharmacology Harvard Medical SchoolBostonMA 02115USA

Stereoselective synthesis of multi-substituted cyclobutanes with different substituents is still a daunting challenge in organic synthesis.We report here a practical and facile approach to synthesizing all-trans 2,3,4-trisubstituted cyclobutanones from readily available dichlorocyclobutanones.The substitution reaction proceeds smoothly via oxyallyl cation intermediates under mild basic conditions.Further transformation to the synthesis of 1,2,3,4-tetrasubstituted cyclobutanes was also explored.

关键词： Diastereoselectivity Modular synthesis Nucleophilic substitution Organohalides Oxyallyl cation Precision functionalization Strained molecules 1,2,3,4-Tetrasubstituted cyclobutanes

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Two distinct subpopulations of marginal zone B cells exhibit differential antibody-producing capacities and radioresistance

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Cellular & Molecular Immunology 2024年第4期21卷 393-408页

作者： Sujin Lee Yeunjung Ko Hyun Woo Lee Won Joon Oh Hun Gi Hong Dinuka Ariyaratne Se Jin Im Tae Jin Kim department of Immunology Graduate School of Basic Medical ScienceSungkyunkwan University School of MedicineSuwon16419Republic of Korea department of Immunology and Molecular Medicine Faculty of Medical SciencesUniversity of Sri JayewardenepuraNugegodaSri Lanka present address:Immunology and Microbiology Graduate Program Baylor College of MedicineHoustonTX77030USA

Marginal zone(MZ)B cells,which are splenic innate-like B cells that rapidly secrete antibodies(Abs)against blood-borne pathogens,are composed of heterogeneous subpopulations.Here,we showed that MZ B cells can be divided into two distinct subpopulations according to their CD80 expression levels.CD80^(high)MZ B cells exhibited greater Ab-producing,proliferative,and IL-10-secreting capacities than did CD80^(low)MZ B cells.Notably,CD80^(high)MZ B cells survived 2-Gy whole-body irradiation,whereas CD80^(low)MZ B cells were depleted by irradiation and then repleted with one month after irradiation.Depletion of CD80^(low)MZ B cells led to accelerated development of type II collagen(CII)-induced arthritis upon immunization with bovine CII.CD80^(high)MZ B cells exhibited higher expression of genes involved in proliferation,plasma cell differentiation,and the antioxidant response.CD80^(high)MZ B cells expressed more autoreactive B cell receptors(BCRs)that recognized double-stranded DNA or CII,expressed more immunoglobulin heavy chain sequences with shorter complementarity-determining region 3 sequences,and included more clonotypes with no N-nucleotides or with B-1a BCR sequences than CD80^(low)MZ B cells.Adoptive transfer experiments showed that CD21^(+)CD23^(+)transitional 2 MZ precursors preferentially generated CD80^(low)MZ B cells and that a proportion of CD80^(low)MZ B cells were converted into CD80^(high)MZ B cells;in contrast,CD80^(high)MZ B cells stably remained CD80^(high)MZ B cells.In summary,MZ B cells can be divided into two subpopulations according to their CD80 expression levels,Ab-producing capacity,radioresistance,and autoreactivity,and these findings may suggest a hierarchical composition of MZ B cells with differential stability and BCR specificity.

关键词： Marginal Zone B Cell CD80 Autoreactivity Radioresistance

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Nanotechnology’s frontier in combatting infectious and inflammatory diseases:prevention and treatment

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Signal Transduction and Targeted Therapy 2024年第3期9卷 998-1047页

作者： Yujing Huang Xiaohan Guo Yi Wu Xingyu Chen Lixiang Feng Na Xie Guobo Shen department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China Hospitaland West China School of Basic Medical Sciences and Forensic MedicineSichuan Universityand Collaborative Innovation Center for BiotherapyChengdu 610041China

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases,which continuously pose one of the most serious threats to human health,attributed to factors such as the emergence of new pathogens,increasing drug resistance,changes in living environments and lifestyles,and the aging population.Despite rapid advancements in mechanistic research and drug development for these diseases,current treatments often have limited efficacy and notable side effects,necessitating the development of more effective and targeted anti-inflammatory therapies.In recent years,the rapid development of nanotechnology has provided crucial technological support for the prevention,treatment,and detection of inflammation-associated diseases.Various types of nanoparticles(NPs)play significant roles,serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability.NPs can also directly combat pathogens and inflammation.In addition,nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases.This review categorizes and characterizes different types of NPs,summarizes their applications in the prevention,treatment,and detection of infectious and inflammatory diseases.It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects.In conclusion,nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.

关键词： prevention inflammatory treatment

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Improving the value of molecular testing:current status and opportunities in colorectal cancer precision medicine

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cancer Biology & Medicine 2024年第1期21卷 21-28页

作者： Haiyun Li Linwei Guo Chenchen Wang Xin Hu Ye Xu department of Colorectal Surgery Fudan University Shanghai Cancer CenterShanghai 200032China department of Oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China department of Gastrointestinal Medical Oncology Fudan University Shanghai Cancer CenterShanghai 200032China Precision cancer Medical center Affiliated with Fudan University Shanghai cancer center Shanghai 201315China

Colorectal cancer(CRC)is the second leading cause of cancer-related deaths worldwide1.Surgical radical resection with adjuvant chemotherapy remains the primary treatment choice for CRC,but the 5-year postoperative survival rate is only approximately 60%,and approximately one-third of patients with CRC experience recurrence within 2 years of surgery2.Fortunately,the transformation of high-throughput sequencing has accelerated the development of precision medicine.For example,KRAS mutations indicate resistance to anti-epidermal growth factor receptor(EGFR)-targeted therapies in CRC3.Furthermore,molecular-guided individualized therapy has brought new promise in major clinical areas and challenges,such as novel biomarkers predicting sensitivity and resistance to immunotherapy for microsatellite stable(MSS)CRC.

关键词： cancer chemotherapy colorectal

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CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

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Journal of Genetics and Genomics 2024年第5期51卷 531-542页

作者： Danhui Ruan Jiancheng Xu Yang Liu Juan Luo Xuyang Zhao Yuhua Li Guangxi Wang Jiawen Feng Hui Liang Yue Yin Jianyuan Luo Yuxin Yin Institute of Systems Biomedicine Department of PathologySchool of Basic Medical SciencesBeijing Key Laboratory of Tumor Systems BiologyPeking University International Cancer InstitutePeking-Tsinghua Center of Life SciencesPeking University Health Science CenterBeijing 100191China Institute of Precision Medicine Peking University Shenzhen HospitalShenzhenGuangdong 518036China department of Pharmacology School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China department of Medical Genetics Center for Medical GeneticsSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Soochow University cancer Institute SuzhouJiangsu 215127China

Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.

关键词： Circular RNA LRPPRC Mitochondrial energy metabolism mtDNApost-transcriptional regulation

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TGF-βsignaling in health,disease,and therapeutics

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1466-1505页

作者： Ziqin Deng Tao Fan Chu Xiao He Tian Yujia Zheng Chunxiang Li Jie He department of Thoracic Surgery National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

ransforming growth factor(TGF)-βis a multifunctional cytokine expressed by almost every tissue and cell type.The signal transduction of TGF-βcan stimulate diverse cellular responses and is particularly critical to embryonic development,wound healing,tissue homeostasis,and immune homeostasis in health.The dysfunction of TGF-βcan play key roles in many diseases,and numerous targeted therapies have been developed to rectify its pathogenic activity.In the past decades,a large number of studies on TGF-βsignaling have been carried out,covering a broad spectrum of topics in health,disease,and therapeutics.Thus,a comprehensive overview of TGF-βsignaling is required for a general picture of the studies in this field.In this review,we retrace the research history of TGF-βand introduce the molecular mechanisms regarding its biosynthesis,activation,and signal transduction.We also provide deep insights into the functions of TGF-βsignaling in physiological conditions as well as in pathological processes.TGF-β-targeting therapies which have brought fresh hope to the treatment of relevant diseases are highlighted.Through the summary of previous knowledge and recent updates,this review aims to provide a systematic understanding of TGF-βsignaling and to attract more attention and interest to this research area.

关键词： homeostasis healing wound

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Prognostic significance of grade of malignancy based on histopathological differentiation and Ki-67 in pancreatic ductal adenocarcinoma

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cancer Biology & Medicine 2024年第5期21卷 416-432页

作者： Yuexiang Liang Guannan Sheng Yu Guo Yiping Zou Hanhan Guo Zhifei Li Shaofei Chang Quan Man Song Gao Jihui Hao department of Pancreatic cancer Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for Cancer Key Laboratory of Cancer Prevention and TherapyTianjin Tianjin's Clinical Research Center for Cancer department of Gastrointestinal Oncology The First Affiliated Hospital of Hainan Medical University department of Gastrointestinal Pancreatic Surgery Shanxi Provincial People's Hospital

Objective: Tumor cell malignancy is indicated by histopathological differentiation and cell proliferation. Ki-67, an indicator of cellular proliferation, has been used for tumor grading and classification in breast cancer and neuroendocrine tumors. However, its prognostic significance in pancreatic ductal adenocarcinoma(PDAC) remains uncertain.Methods: Patients who underwent radical pancreatectomy for PDAC were retrospectively enrolled, and relevant prognostic factors were examined. Grade of malignancy(GOM), a novel index based on histopathological differentiation and Ki-67, is proposed, and its clinical significance was evaluated.Results: The optimal threshold for Ki-67 was determined to be 30%. Patients with a Ki-67 expression level > 30% rather than ≤ 30% had significantly shorter 5-year overall survival(OS) and recurrence-free survival(RFS). In multivariate analysis, both histopathological differentiation and Ki-67 were identified as independent prognostic factors for OS and RFS. The GOM was used to independently stratify OS and RFS into 3 tiers, regardless of TNM stage and other established prognostic factors. The tumor-nodemetastasis-GOM stage was used to stratify survival into 5 distinct tiers, and surpassed the predictive performance of TNM stage for OS and RFS.Conclusions: Ki-67 is a valuable prognostic indicator for PDAC. Inclusion of the GOM in the TNM staging system may potentially enhance prognostic accuracy for PDAC.

关键词： Ki-67 Pancreatic ductal adenocarcinoma TNM stage differentiation prognosis

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Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin

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Science China(Life Sciences) 2024年第6期67卷 1226-1241页

作者： Zhengyang Guo Jiaqi Huang Xiao Huo Chen Huang Xiaotong Yu Yan Sun Yanfang Li Tianhui He Hongyan Guo Jianling Yang Lixiang Xue cancer center of Peking University Third Hospital Beijing 100191China center of basic Medical Research Institute of Medical Innovation and ResearchPeking University Third HospitalBeijing 100191China Peking University Third Hospital cancer center Department of Radiation OncologyPeking University Third HospitalBeijing 100191China department of Obstetrics and Gynecology Peking University Third HospitalBeijing 100191China

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late.In ovarian cancer,multiple metabolic enzymes of lipid metabolism are abnormally expressed,resulting in metabolism disorder.As a characteristic pathway in polyunsaturated fatty acid(PUFA)metabolism,arachidonic acid(AA)metabolism is disturbed in ovarian cancer.Therefore,we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes.This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms(TCGA,ICGC,and GSE17260).The high association between the risk subgroups and clinical characteristics indicated a good performance of the model.Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer.Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer.Additionally,our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis,which contributes to the reduction of tumor-infiltrating CD8+T cells and immune escape in ovarian cancer.These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.

关键词： ovarian cancer polyunsaturated fatty acids prognostic risk model LTA4H tumor immunity CCL5

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The evolution of cancer genomic medicine in Japan and the role of the National cancer center Japan

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cancer Biology & Medicine 2024年第1期21卷 29-44页

作者： Teruhiko Yoshida Yasushi Yatabe Ken Kato Genichiro Ishii Akinobu Hamada Hiroyuki Mano Kuniko Sunami Noboru Yamamoto Takashi Kohno department of Genetic Medicine and Services National Cancer Center HospitalTokyo 104-0045Japan department of Diagnostic Pathology National Cancer Center HospitalTokyo 104-0045Japan Clinical Research Support Offce Clinical Research Coordinating SectionBiobank Translational Research Support SectionNational Cancer Center HospitalTokyo 104-0045Japan department of Pathology and Clinical Laboratories National Cancer Center Hospital EastChiba 277-8577Japan Division of Molecular Pharmacology National Cancer Center Research InstituteTokyo 104-0045Japan National cancer center Research Institute Tokyo 104-0045Japan department of Laboratory Medicine National Cancer Center HospitalTokyo 104-0045Japan department of Experimental Therapeutics National Cancer Center HospitalTokyo 104-0045Japan Division of Genome Biology National Cancer Center Research InstituteTokyo 104-0045Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National cancer center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

关键词： cancer genomic medicine biobank patient-derived xenograft multi-gene panel test whole genome sequencing

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