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Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma

National Science Review 2024年第5期11卷 170-185页

作者： Yong Zhou Shanlan Mo Heyang Cui Ruifang Sun Weimin Zhang Xiaofei Zhuang Enwei Xu Hongyi Li Yikun Cheng Yongsheng Meng Meilin Liu Ting Yan Huijuan Liu Ling Zhang Bin Yang Yanfeng Xi Shubin Wang Xiaolong Cheng Shuai Cheng Li Zhihua Liu Qimin Zhan Zheng Hu Yongping Cui cancer Institute Department of Pathology Peking University Shenzhen Hospital Shenzhen Peking University-the Hong Kong University of Science and Technology(PKU-HKUST) Medical Center Institute of Cancer ResearchShenzhen Bay Laboratory Key laboratory of Cellular Physiology of the Ministry of Education Department of Pathology Shanxi Medical University City University of Hong Kong Shenzhen Research Institute CAS Key laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institute of Advanced TechnologyChinese Academy of Sciences Department of Surgery Faculty of Medicine The Chinese University of Hong Kong Department of Tumor Biobank Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Research Unit of Molecular cancer Research Chinese Academy of Medical Sciences Department of Thoracic Surgery Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University Department of Pathology Shanxi Province Cancer HospitalShanxi Hospital Affiliated to Cancer HospitalChinese Academy of Medical SciencesCancer Hospital Affiliated to Shanxi Medical University College of Letters & Science University of California Berkeley State Key laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College

Esophageal squamous cell carcinoma（ESCC） is a poor-prognostic cancer type with extensive intra-and inter-patient heterogeneity in both genomic variations and tumor microenvironment（TME）. However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2,accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the ***, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted ***, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.

关键词： squamous cell carcinoma heterogeneity multi-omics evolution tumor microenvironment

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Exploring the potential of extrachromosomal DNA as a novel oncogenic driver

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Science China Life Sciences 2024年

作者： Huanbo Zhu Longtao Huangfu Junbing Chen Jiafu Ji Xiaofang Xing Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Division of Gastrointestinal Cancer Translational Research Laboratory Peking University Cancer Hospital &Institute Department of Gastrointestinal cancer Center Peking University Cancer Hospital & Institute Department of Liver Surgery & Transplantation Liver Cancer Institute Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education State Key laboratory of Holistic Integrative Management of Gastrointestinal cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Division of Gastrointestinal Cancer Translational Research Laboratory Peking University Cancer Hospital & Institute

Extrachromosomal DNA(ecDNA) is a form of circular DNA mostly found in tumor cells. Unlike the typical chromosomal DNA, ecDNA is circular, self-replicating, and carries complete or partial gene fragments. Although ecDNA occurrence remains a rare event in cancer, recent studies have shown that oncogene amplification on ecDNA is widespread throughout many types of cancer, implying that ecDNA plays a central role in accelerating tumor evolution. ecDNA has also been associated with increased tumor mutation burden, chromosomal instability, and even tumor microenvironment remodeling. ecDNA may be crucial in influencing tumor heterogeneity, drug sensitivity,oncogenic senescence, and tumor immunogenicity, leading to a worsening prognosis for tumor patients. In this way, several clinical trials have been conducted to investigate the importance of ecDNA in clinical treatment. In this review, we summarize the biogenesis, characteristics, and current research methods of ecDNA, discuss the vital role of ecDNA-caused tumor heterogeneity in cancers, and highlight the potential role of ecDNA in cancer therapy.

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The two sides of chromosomal instability:drivers and brakes in cancer

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1595-1624页

作者： Rendy Hosea Sharon Hillary Sumera Naqvi Shourong Wu Vivi Kasim Key laboratory of Biorheological Science and Technology Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400045China The 111 Project laboratory of Biomechanics and Tissue Repair College of BioengineeringChongqing UniversityChongqing 400044China Chongqing Key laboratory of Translational Research for cancer Metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing UniversityChongqing 400030China

Chromosomal instability(CIN)is a hallmark of cancer and is associated with tumor cell *** triggers a chain reaction in cells leading to chromosomal abnormalities,including deviations from the normal chromosome number or structural changes in *** arises from errors in DNA replication and chromosome segregation during cell division,leading to the formation of cells with abnormal number and/or structure of *** in DNA replication result from abnormal replication licensing as well as replication stress,such as double-strand breaks and stalled replication forks;meanwhile,errors in chromosome segregation stem from defects in chromosome segregation machinery,including centrosome amplification,erroneous microtubule-kinetochore attachments,spindle assembly checkpoint,or defective sister chromatids *** normal cells,CiN is deleterious and is associated with DNA damage,proteotoxic stress,metabolic alteration,cell cycle arrest,and ***,despite these negative consequences,CiN is one of the hallmarks of cancer found in over 90%of solid tumors and in blood ***,CiN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity,thereby facilitating adaptive resistance to therapies;however,excessive CiN could induce tumor cells death,leading to the"just-right"model for CIN in *** the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor *** review provides an overview of causes and consequences of CIN,as well as the paradox of CIN,a phenomenon that continues to perplex ***,this review explores the potential of CIN-based anti-tumor therapy.

关键词： chromosomal consequences thereby

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Gas-generating polymersomes-based amplified photoimmunotherapy for abscopal effect and tumor metastasis inhibition

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Chinese Chemical Letters 2024年第6期35卷 456-461页

作者： Chenlu Huang Xinyu Yang Qingyu Yu Linhua Zhang Dunwan Zhu Tianjin Key laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer ImmunotherapyInstitute of Biomedical EngineeringChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300192China

Due to the heterogeneity of tumors,single phototherapy cannot completely ablate tumors and inhibit tumor *** overcome these,we formulated targeted and multifunctional polymersomes ABC@ICGIMQ-LHRH(AIRL)that encapsulated Toll-like receptor(TLR)7/8 agonist imiquimod(IMQ)and photosensitizer indocyanine green(ICG)in the hydrophobic layer as well as bubble-generator NH_(4)HCO_(3) in the hydrophilic cavity to inhibit the growth of primary and distant tumors,and prevent tumor metastasis through synergistic *** AIRL polymersomes exhibited uniform and stable size,and high drug encapsulation efficiency,acid/reduction/laser responsiveness,excellent photothermal conversion efficiency,effective reactive oxygen species generation,high tumor *** could be effectively internalized by dendritic cells(DCs),achieve lysosome escape and enhance DCs *** synergistic photoimmunotherapy via AIRL polymersomes remarkably promoted the differentiation and activation of T cells,elevated strong systemic immune response to eradicate primary tumors and inhibit the growth of distant ***,the endurable immunological memory prevented tumor metastasis,which provided a promising nanoplatform for the combination therapy of cancer.

关键词： Polymersomes Phototherapy Immunotherapy TLR 7/8 agonist Gas-generating

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Systematic review of risk factors,prognosis,and management of colorectal signet-ring cell carcinoma

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 2141-2158页

作者： Frederiek Nuytens Vincent Drubay Clarisse Eveno Florence Renaud Guillaume Piessen Department of Digestive and Oncological Surgery University LilleClaude Huriez University HospitalLille 59000France Department of Digestive and Hepatobiliary/Pancreatic Surgery AZ GroeningeKortrijk 8500Belgium Cambrai Hospital Center and Sainte Marie Group of Hospitals of The Catholic Institute of LilleCambrai 59400France CNRS InsermUMR9020-U1277-CANTHER-CancerUniversity LilleCHU LilleLille 59000France

BACKGROUND Colorectal signet-ring cell carcinoma(CSRCC)is a rare clinical entity which accounts for approximately 1%of all colorectal *** multiple studies concerning this specific topic have been published in the past decades,the pathogenesis,associated risk factors,and potential implications on treatment are still poorly *** the low incidence,historically confusing histological criteria have resulted in confusing ***,the rising incidence of CSRCC along with relatively young age at presentation and associated dismal prognosis,highlight the actual interest to synthesize the known literature regarding *** To provide an updated overview of risk factors,prognosis,and management of *** A literature search in the MEDLINE/PubMed database was conducted with the following search terms used:‘Signet ring cell carcinoma’and‘colorectal’.Studies in English language,published after January 1980,were *** included in the qualitative synthesis were evaluated for content concerning epidemiology,risk factors,and clinical,diagnostic,histological,and molecular features,as well as metastatic pattern and therapeutic *** possible,presented data was extracted in order to present a more detailed overview of the *** In total,67 articles were included for qualitative analysis,of which 54 were eligible for detailed data *** has a reported incidence between 0.1%-2.4%and frequently presents with advanced disease stage at the time of *** is associated with an impaired overall survival(5-year OS:0%-46%)and a worse stagecorrected outcome compared to mucinous and not otherwise specified *** systematic use of exploratory laparoscopy to determine the presence of peritoneal metastases has been *** is the mainstay of treatment,although the rates of curative resection in CSRCC(21%-82%)are lower compared to those in other histological *** case of peritoneal

关键词： Colorectal cancer Signet-ring cell histology Poorly cohesive cells Systematic review Risk factors Prognosis Therapeutic management

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The heterogeneity of tumor-associated macrophages and strategies to target it

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BIOCELL 2024年第3期48卷 363-378页

作者： HAO LV BO ZHU DEGAO CHEN Institute of cancer Xinqiao HospitalThird Military Medical UniversityChongqing400037China Chongqing Key laboratory of Immunotherapy Xinqiao HospitalThird Military Medical UniversityChongqing400037China

Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor *** studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical ***,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their ***,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor *** review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.

关键词： Tumor-associated macrophages Tissue-resident macrophages heterogeneity Immune checkpoint therapy

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Circulating tumor cells shielded with extracellular vesicle-derived CD45 evade T cell attack to enable metastasis

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2114-2131页

作者： Chuan Yang Xueping Wang Kenneth K.W.To Caimei Cui Min Luo Shaocong Wu Lamei Huang Kai Fu Can Pan Zeyu Liu Teng Fan Caibo Yang Fang Wang Liwu Fu State Key laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510060P.R.China School of Pharmacy Faculty of MedicineThe Chinese University of Hong KongHong KongChina LABVIV Technology(Shenzhen)Co. LtdShenzhen 518057China

Circulating tumor cells(CTCs)are precursors of distant metastasis in a subset of cancer patients.A better understanding of CTCs heterogeneity and how these CTCs survive during hematogenous dissemination could lay the foundation for therapeutic prevention of cancer *** remains elusive how CTCs evade immune surveillance and elimination by immune *** this study,we unequivocally identified a subpopulation of CTCs shielded with extracellular vesicle(EVs)-derived CD45(termed as CD45^(+)CTCs)that resisted T cell attack.A higher percentage of CD45^(+)CTCs was found to be closely correlated with higher incidence of metastasis and worse prognosis in cancer ***,CD45^(+)tumor cells orchestrated an immunosuppressive milieu and CD45^(+)CTCs exhibited remarkably stronger metastatic potential than CD45−CTCs in ***,CD45 expressing on tumor surfaces was shown to form intercellular CD45-CD45 homophilic interactions with CD45 on T cells,thereby preventing CD45 exclusion from TCR-pMHC synapse and leading to diminished TCR signaling transduction and suppressed immune ***,these results pointed to an underappreciated capability of EVs-derived CD45-dressed CTCs in immune evasion and metastasis,providing a rationale for targeting EVs-derived CD45 internalization by CTCs to prevent cancer metastasis.

关键词： CD45 metastasis prevention

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Deep learning framework for comprehensive molecular and prognostic stratifications of triple-negative breast cancer

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Fundamental Research 2024年第3期4卷 678-689页

作者： Shen Zhao Chao-Yang Yan Hong Lv Jing-Cheng Yang Chao You Zi-Ang Li Ding Ma Yi Xiao Jia Hu Wen-Tao Yang Yi-Zhou Jiang Jun Xu Zhi-Ming Shao Key laboratory of Breast cancer in Shanghai Department of Breast SurgeryFudan University Shanghai Cancer CenterShanghai 200032China Institute for AI in Medicine School of Artificial IntelligenceNanjing University of Information Science and TechnologyNanjing 210044China Department of Pathology Fudan University Shanghai Cancer CenterShanghai 200032China Greater Bay Area Institute of Precision Medicine Guangzhou 511466China Department of Radiology Fudan University Shanghai Cancer CenterShanghai 200032China

Triple-negative breast cancer(TNBC)is the most challenging breast cancer *** stratification and target therapy bring clinical benefit for TNBC patients,but it is difficult to implement comprehensive molecular testing in clinical ***,using our multi-omics TNBC cohort(N=425),a deep learning-based framework was devised and validated for comprehensive predictions of molecular features,subtypes and prognosis from pathological whole slide *** framework first incorporated a neural network to decompose the tissue on WSIs,followed by a second one which was trained based on certain tissue types for predicting different ***-omics molecular features were analyzed including somatic mutations,copy number alterations,germline mutations,biological pathway activities,metabolomics features and immunotherapy *** was shown that the molecular features with therapeutic implications can be predicted including the somatic PIK3CA mutation,germline BRCA2 mutation and PD-L1 protein expression(area under the curve[AUC]:0.78,0.79 and 0.74 respectively).The molecular subtypes of TNBC can be identified(AUC:0.84,0.85,0.93 and 0.73 for the basal-like immune-suppressed,immunomodulatory,luminal androgen receptor,and mesenchymal-like subtypes respectively)and their distinctive morphological patterns were revealed,which provided novel insights into the heterogeneity of TNBC.A neural network integrating image features and clinical covariates stratified patients into groups with different survival outcomes(log-rank P<0.001).Our prediction framework and neural network models were externally validated on the TNBC cases from TCGA(N=143)and appeared robust to the changes in patient *** potential clinical translation,we built a novel online platform,where we modularized and deployed our framework along with the validated *** can realize real-time one-stop prediction for new *** summary,using only pathological WSIs,our proposed framework

关键词： Triple-negative breast cancer Deep learning Digital pathology Patient stratification Online platform

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Modeling human gastric cancers in immunocompetent mice

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cancer Biology & Medicine 2024年第7期21卷 553-570页

作者： Weihong Zhang Shilong Wang Hui Zhang Yan Meng Shi Jiao Liwei An Zhaocai Zhou Department of Stomatology Department of Medical UltrasoundShanghai Tenth People's HospitalTongji University Cancer CenterTongji University School of MedicineShanghai 200072China State Key laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200032China Collaborative Innovation Center for cancer Personalized Medicine School of Public HealthNanjing Medical UniversityNanjing 211166China

Gastric cancer(GC)is a major cause of cancer-related mortality *** is determined by multiple(epi)genetic and environmental factors;can occur at distinct anatomic positions of the stomach;and displays high heterogeneity,with different cellular origins and diverse histological and molecular *** heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient *** the past decade,great progress has been made in the study of GC,particularly in molecular subtyping,investigation of the immune microenvironment,and defining the evolutionary path and *** mouse models,particularly immunocompetent models that mimic the cellular and molecular features of human GC,in combination with organoid culture and clinical studies,have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion,and the development of novel therapeutic ***,we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models,emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.

关键词： Gastric cancer heterogeneity mouse model GEMM immunocompetent

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Complex role of neutrophils in the tumor microenvironment: an avenue for novel immunotherapies

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cancer Biology & Medicine 2024年第10期 849-863页

作者： Mao Zhang Haokai Qin Yingcheng Wu Qiang Gao Department of Liver Surgery and Transplantation Liver Cancer Institute and Zhongshan Hospital State Key Laboratory of Genetic Engineering Human Phenome Institute Fudan University

Neutrophils, which originate from the bone marrow and are characterized by a segmented nucleus and a brief lifespan, have a crucial role in the body's defense against infections and acute inflammation. Recent research has uncovered the complex roles of neutrophils as regulators in tumorigenesis, during which neutrophils exhibit a dualistic nature that promotes or inhibits tumor progression. This adaptability is pivotal within the tumor microenvironment(TME). In this review, we provide a comprehensive characterization of neutrophil plasticity and heterogeneity, aiming to illuminate current research findings and discuss potential therapeutic avenues. By delineating the intricate interplay of neutrophils in the TME, this review further underscores the urgent need to understand the dual functions of neutrophils with particular emphasis on the anti-tumor effects to facilitate the development of effective therapeutic strategies against cancer.

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