Organoids are three-dimensional culture systems generated from embryonic stem cells,induced pluripotent stem cells,and adult stem cells.They are capable of cell proliferation,differentiation,and self-renewal.Upon stim...Organoids are three-dimensional culture systems generated from embryonic stem cells,induced pluripotent stem cells,and adult stem cells.They are capable of cell proliferation,differentiation,and self-renewal.Upon stimulation by signal factors and/or growth factors,organoids self-assemble to replicate the morphological and structural characteristics of the corresponding organs.They provide an extraordinary platform for investigating organ development and mimicking pathological processes.Organoid biobanks derived from a wide range of carcinomas have been established to represent different lesions or stages of clinical tumors.Importantly,genomic and transcriptomic analyses have confirmed maintenance of intra-and interpatient heterogeneities in organoids.Therefore,this technology has the potential to revolutionize drug screening and personalized medicine.In this review,we summarized the characteristics and applications of organoids in cancer research by the establishment of organoid biobanks directly from tumor organoids or from genetically modified non-cancerous organoids.We also analyzed the current state of organoid applications in drug screening and personalized medicine.展开更多
Objective:Liver cancer is a deadly malignancy associated with high mortality and morbidity.Less than 20%of patients with advanced liver cancer respond to a single anti-PD-1 treatment.The high heterogeneity of neutroph...Objective:Liver cancer is a deadly malignancy associated with high mortality and morbidity.Less than 20%of patients with advanced liver cancer respond to a single anti-PD-1 treatment.The high heterogeneity of neutrophils in the tumor immune microenvironment in liver cancer may contribute to resistance to immune checkpoint blockade(ICB).However,the underlying mechanism remains largely unknown.Methods:We established an orthotopic liver cancer model by using transposable elements to integrate the oncogenes Myc and KrasG12Dinto the genome in liver cells from conditional Trp53 null/null mice(pTMK/Trp53^(-/-)).Flow cytometry and immunohistochemistry were used to assess the changes in immune cells in the tumor microenvironment.An ex vivo coculture assay was performed to test the inhibitory effects of tumor-associated neutrophils(TANs)on CD8^(+)T cells.The roles of neutrophils,T cells,and NK cells were validated through antibody-mediated depletion.The efficacy of the combination of neutrophil depletion and ICB was evaluated.Results:Orthotropic pTMK/Trp53^(-/-)mouse liver tumors displayed a moderate response to anti-Ly6G treatment but not PD-1 blockade.Depletion of neutrophils increased the infiltration of CD8^(+)T cells and decreased the number of exhausted T cells in the tumor microenvironment.Furthermore,depletion of either CD8^(+)T or NK cells abrogated the antitumor efficacy of anti-Ly6G treatment.Moreover,the combination of anti-Ly6G with anti-PD-L1 enhanced the infiltration of cytotoxic CD8^(+)T cells and thereafter resulted in a significantly greater decrease in tumor burden.Conclusions:Our data suggest that TANs may contribute to the resistance of liver cancer to ICB,and combining TAN depletion with T cell immunotherapy synergistically increases antitumor efficacy.展开更多
The liver is the largest solid organ,and it is involved in multiple biological processes,including energy metabolism,protein synthesis,and detoxification1.Under physiological or pathological conditions,the liver can r...The liver is the largest solid organ,and it is involved in multiple biological processes,including energy metabolism,protein synthesis,and detoxification1.Under physiological or pathological conditions,the liver can regrow to normal size even after resection of 90%of the liver volume because of its strong regeneration ability2.Changes in diet,viral infection(HBV and/or HCV)。展开更多
Epigenetic dysregulation is a key factor leading to oncogenesis and tumor progression1. To date, seven agents in three epigenetic target classes have been approved by the U.S. Food and Drug Administration for the trea...Epigenetic dysregulation is a key factor leading to oncogenesis and tumor progression1. To date, seven agents in three epigenetic target classes have been approved by the U.S. Food and Drug Administration for the treatment of diverse malignancies. Despite this approval for clinical application, the mechanisms of many epigenetic modulators are not completely understood, because many genes are epigenetically regulated.展开更多
Viewing cancer as a large,evolving population of heterogeneous cells is a common perspective.Because genomic instability is one of the fundamental features of cancer,this intrinsic tendency of genomic variation leads ...Viewing cancer as a large,evolving population of heterogeneous cells is a common perspective.Because genomic instability is one of the fundamental features of cancer,this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation,development,metastasis,and relapse.With the increased mutation rate and abundant diversity of the gene pool,this heterogeneity leads to cancer evolution,which is the major obstacle in the clinical treatment of cancer.Cells rely on the integrity of DNA repair machineries to maintain genomic stability,but these machineries often do not function properly in cancer cells.The deficiency of DNA repair could contribute to the generation of cancer genomic instability,and ultimately promote cancer evolution.With the rapid advance of new technologies,such as single-cell sequencing in recent years,we have the opportunity to better understand the specific processes and mechanisms of cancer evolution,and让s relationship with DNA repair.Here,we review recent findings on how DNA repair affects cancer evolution,and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.展开更多
Objective: Cancer immunotherapy has made remarkable advances in recent years, but its effectiveness in treating gastric cancer is often limited by the complexity of the tumor microenvironment and the lack of effective...Objective: Cancer immunotherapy has made remarkable advances in recent years, but its effectiveness in treating gastric cancer is often limited by the complexity of the tumor microenvironment and the lack of effective biomarkers. This study aimed to identify effective biomarkers for immunotherapy treatment by characterizing the tumor microenvironment.Methods: We retrieved the RNA-seq data from gastric cancer patients treated with the programmed death 1(PD-1) blockade pembrolizumab. Differentially expressed genes associated with clinical outcomes were identified and further analyzed using gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis. Gene signature scores were calculated by single sample Gene Set Enrichment Analysis(ssGSEA). The infiltration levels of immune cells were quantified using the xCell website. Cell type enrichment analysis was performed to compare treatment response and non-response groups, and regression analysis was used to investigate the relationship between interferon gamma(IFNγ) immune response and immune cell infiltration. Biomarkers were identified using least absolute shrinkage and selection operator(LASSO) analysis.Results: Compared to normal tissues, cytokine activity and interleukin-6 production were highly activated in gastric tumors. Responders to pembrolizumab showed significantly up-regulated expression of IFNγ responserelated genes. Cell type enrichment analysis revealed that Th1 cells were significantly enriched in the tumor microenvironment of responders. Regression analysis indicated that Th1 cells induced IFNγ response more efficiently than other cell types. Using signatures of Th1 cells, stromal cells and IFNγ response, a set of eight genes were identified that effectively predicted the efficacy of immunotherapy treatment and patient prognosis.Conclusions: Th1 cells promote therapeutic efficacy of PD-1 blockade by promoting IFNγ immune response in gastric cancer. The identified biomarkers have the potential to improve the effectiveness of immunotherapy treatment for gastric cancer patients.展开更多
Introduction Primary liver cancer, the second most common cause of cancer related death worldwide, presents ethnic, etiological, sex, and geographical diversity2 （Figure 1A）. At the histological level, liver cancer ...Introduction Primary liver cancer, the second most common cause of cancer related death worldwide, presents ethnic, etiological, sex, and geographical diversity2 （Figure 1A）. At the histological level, liver cancer includes two major types： hepatocellular carcinoma （HCC, about 80%） and cholangiocarcinoma （CCA, about 15%）. Many etiological factors contribute to HCC development, such as hepatitis B virus （HBV）, hepatitis C virus （HCV）, aflatoxin B1 （AFB1）, alcohol, and metabolic diseases3. By contrast, the major risk factors for CCA are liver flukes （Opisthorchis viverrini and Clonorchis sinensis） and primary sclerosing cholangitis4,展开更多
Recently,an original article tided“A patient-derived glioblastoma organoid model and biobank recapitulates inter-and intra-tumoral heterogeneity”was published in Cell(1),a leading journal of scientific research worl...Recently,an original article tided“A patient-derived glioblastoma organoid model and biobank recapitulates inter-and intra-tumoral heterogeneity”was published in Cell(1),a leading journal of scientific research worldwide.This paper reported that Fadi Jacob and colleagues established an organoids biobank with patient-derived glioblastoma organoids(GBOs),recapitulating the histological features,cellular diversity,gene expression and mutational profiles of their corresponding parental tumors.And functions of these organoids were confirmed both in vitro and in vivo xenograft models.In addition,by modeling targeted drug testing and chimeric antigen receptor T cell(CAR-T)immunotherapy,they demonstrated the application of GBOs in personalized medicine(1)(Figure 1).展开更多
Objective: Previous investigations of circulating tumor cells(CTCs) have mainly focused on their genomic or transcriptomic features, leaving their epigenetic landscape relatively uncharacterized. Here, we investigated...Objective: Previous investigations of circulating tumor cells(CTCs) have mainly focused on their genomic or transcriptomic features, leaving their epigenetic landscape relatively uncharacterized. Here, we investigated the genome-wide DNA methylome of CTCs with a view to understanding the epigenetic regulatory mechanisms underlying cancer metastasis.Methods: We evaluated single-cell DNA methylome and copy number alteration(CNA) in 196 single cells,including 107 CTCs collected from 17 cancer patients covering six different cancer types. Our single-cell bisulfite sequencing(sc BS-seq) covered on average 11.78% of all Cp G dinucleotides and accurately deduced the CNA patterns at 500 kb resolution.Results: We report distinct subclonal structures and different evolutionary histories of CTCs inferred from CNA and DNA methylation profiles. Furthermore, we demonstrate potential tumor origin classification based on the tissue-specific DNA methylation profiles of CTCs.Conclusions: Our work provides a comprehensive survey of genome-wide DNA methylome in single CTCs and reveals 5-methylcytosine(5-m C) heterogeneity in CTCs, addressing the potential epigenetic regulatory mechanisms underlying cancer metastasis and facilitating the future clinical application of CTCs.展开更多
Introduction As one of the most frequently diagnosed devastating diseases, liver failure is responsible for approximately two million deaths annually worldwide with poor prognosis1. Although liver transplantation has ...Introduction As one of the most frequently diagnosed devastating diseases, liver failure is responsible for approximately two million deaths annually worldwide with poor prognosis1. Although liver transplantation has been developed for the most effective treatment for liver failure, it is far from demands for patients due to the shortage of high-quality donor livers and expensive treatment costs. Currently, with the development of cell therapy, cell transplantations including primary human hepatocytes (PHHs), human hepatocyte-like cells (HLCs) and liver organoids are emerging as great potential tools to alleviate this growing burden.展开更多
Immune checkpoint blockade therapy,which targets T cells to enhance the antitumor immune response,has become a promising treatment for many cancer types1,2.Till now,a total of 6 checkpoint inhibitors targeting cytotox...Immune checkpoint blockade therapy,which targets T cells to enhance the antitumor immune response,has become a promising treatment for many cancer types1,2.Till now,a total of 6 checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4(CTLA-4)。展开更多
Hepatobiliary tumors are of high grade of heterogeneity, which is recognized as a key contributor to drug resistance and poor disease prognosis. However, the intrinsic mechanism between heterogeneity and drug response...Hepatobiliary tumors are of high grade of heterogeneity, which is recognized as a key contributor to drug resistance and poor disease prognosis. However, the intrinsic mechanism between heterogeneity and drug response in hepatobiliary tumor is still largely unknown. Using tumor organoid models, Wang and her colleagues have found that cooperation among distinct subpopulations might be a key mechanism for drug resistance in hepatobiliary tumor.展开更多
Primary liver cancer(PLC)is a fatal disease that affects millions of lives worldwide.PLC is the leading cause of cancer-related deaths and the incidence rate is predicted to rise in the coming decades.PLC can be categ...Primary liver cancer(PLC)is a fatal disease that affects millions of lives worldwide.PLC is the leading cause of cancer-related deaths and the incidence rate is predicted to rise in the coming decades.PLC can be categorized into three major histological subtypes:hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(ICC),and combined HCC-ICC.These subtypes are distinct with respect to epidemiology,clinicopathological features,genetic alterations,and clinical managements,which are thoroughly summarized in this review.The state of treatment strategies for each subtype,including the currently approved drugs and the potential novel therapies,are also discussed.展开更多
Cytokine storms are crucial in the development of various inflammatory diseases,including sepsis and autoimmune disorders.The immunosuppressive cytokine INTERLEUKIN(IL)-37 consists of five isoforms(IL-37a-e).We identi...Cytokine storms are crucial in the development of various inflammatory diseases,including sepsis and autoimmune disorders.The immunosuppressive cytokine INTERLEUKIN(IL)-37 consists of five isoforms(IL-37a-e).We identified IL-37a as a nuclear cytokine for the first time.Compared to IL-37b,IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock.The full-length(FL)form of IL-37a and the N-terminal fragment,which is processed by elastase,could translocate into cell nuclei through a distinctive nuclear localization sequence(NLS)/importin nuclear transport pathway.These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor(PPARγ).This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβand H3K4me1/2 to the enhancer/promoter of Pparg.The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγaxis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases,including sepsis.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.31671421,82030079,and 82003187).
文摘Organoids are three-dimensional culture systems generated from embryonic stem cells,induced pluripotent stem cells,and adult stem cells.They are capable of cell proliferation,differentiation,and self-renewal.Upon stimulation by signal factors and/or growth factors,organoids self-assemble to replicate the morphological and structural characteristics of the corresponding organs.They provide an extraordinary platform for investigating organ development and mimicking pathological processes.Organoid biobanks derived from a wide range of carcinomas have been established to represent different lesions or stages of clinical tumors.Importantly,genomic and transcriptomic analyses have confirmed maintenance of intra-and interpatient heterogeneities in organoids.Therefore,this technology has the potential to revolutionize drug screening and personalized medicine.In this review,we summarized the characteristics and applications of organoids in cancer research by the establishment of organoid biobanks directly from tumor organoids or from genetically modified non-cancerous organoids.We also analyzed the current state of organoid applications in drug screening and personalized medicine.
基金jointly supported by the National Natural Science Foundation of China(Grant Nos.81972735,82030079,and 81972656)Beijing Natural Science Foundation(Grant No.7212108)+2 种基金Michigan Medicine and PKU-HSC JI(Grant No.BMU2020JI005)Baidu Foundation(Grant No.2020BD015)Ying Shi Foundation。
文摘Objective:Liver cancer is a deadly malignancy associated with high mortality and morbidity.Less than 20%of patients with advanced liver cancer respond to a single anti-PD-1 treatment.The high heterogeneity of neutrophils in the tumor immune microenvironment in liver cancer may contribute to resistance to immune checkpoint blockade(ICB).However,the underlying mechanism remains largely unknown.Methods:We established an orthotopic liver cancer model by using transposable elements to integrate the oncogenes Myc and KrasG12Dinto the genome in liver cells from conditional Trp53 null/null mice(pTMK/Trp53^(-/-)).Flow cytometry and immunohistochemistry were used to assess the changes in immune cells in the tumor microenvironment.An ex vivo coculture assay was performed to test the inhibitory effects of tumor-associated neutrophils(TANs)on CD8^(+)T cells.The roles of neutrophils,T cells,and NK cells were validated through antibody-mediated depletion.The efficacy of the combination of neutrophil depletion and ICB was evaluated.Results:Orthotropic pTMK/Trp53^(-/-)mouse liver tumors displayed a moderate response to anti-Ly6G treatment but not PD-1 blockade.Depletion of neutrophils increased the infiltration of CD8^(+)T cells and decreased the number of exhausted T cells in the tumor microenvironment.Furthermore,depletion of either CD8^(+)T or NK cells abrogated the antitumor efficacy of anti-Ly6G treatment.Moreover,the combination of anti-Ly6G with anti-PD-L1 enhanced the infiltration of cytotoxic CD8^(+)T cells and thereafter resulted in a significantly greater decrease in tumor burden.Conclusions:Our data suggest that TANs may contribute to the resistance of liver cancer to ICB,and combining TAN depletion with T cell immunotherapy synergistically increases antitumor efficacy.
基金supported by grants from the National Natural Science Foundation of China(Grant No.81970459)。
文摘The liver is the largest solid organ,and it is involved in multiple biological processes,including energy metabolism,protein synthesis,and detoxification1.Under physiological or pathological conditions,the liver can regrow to normal size even after resection of 90%of the liver volume because of its strong regeneration ability2.Changes in diet,viral infection(HBV and/or HCV)。
文摘Epigenetic dysregulation is a key factor leading to oncogenesis and tumor progression1. To date, seven agents in three epigenetic target classes have been approved by the U.S. Food and Drug Administration for the treatment of diverse malignancies. Despite this approval for clinical application, the mechanisms of many epigenetic modulators are not completely understood, because many genes are epigenetically regulated.
基金supported by the National Natural Science Foundation of China(Grant Nos.81672981 and 81972240).
文摘Viewing cancer as a large,evolving population of heterogeneous cells is a common perspective.Because genomic instability is one of the fundamental features of cancer,this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation,development,metastasis,and relapse.With the increased mutation rate and abundant diversity of the gene pool,this heterogeneity leads to cancer evolution,which is the major obstacle in the clinical treatment of cancer.Cells rely on the integrity of DNA repair machineries to maintain genomic stability,but these machineries often do not function properly in cancer cells.The deficiency of DNA repair could contribute to the generation of cancer genomic instability,and ultimately promote cancer evolution.With the rapid advance of new technologies,such as single-cell sequencing in recent years,we have the opportunity to better understand the specific processes and mechanisms of cancer evolution,and让s relationship with DNA repair.Here,we review recent findings on how DNA repair affects cancer evolution,and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.
基金financially supported by the National Natural Science Foundation of China (No. 82030079, 82341005, 81972656 and 82173035)the National Science and Technology Major Project of China (No. 2022YFC3400 901)Sino-Russian Math Center in PKU。
文摘Objective: Cancer immunotherapy has made remarkable advances in recent years, but its effectiveness in treating gastric cancer is often limited by the complexity of the tumor microenvironment and the lack of effective biomarkers. This study aimed to identify effective biomarkers for immunotherapy treatment by characterizing the tumor microenvironment.Methods: We retrieved the RNA-seq data from gastric cancer patients treated with the programmed death 1(PD-1) blockade pembrolizumab. Differentially expressed genes associated with clinical outcomes were identified and further analyzed using gene ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis. Gene signature scores were calculated by single sample Gene Set Enrichment Analysis(ssGSEA). The infiltration levels of immune cells were quantified using the xCell website. Cell type enrichment analysis was performed to compare treatment response and non-response groups, and regression analysis was used to investigate the relationship between interferon gamma(IFNγ) immune response and immune cell infiltration. Biomarkers were identified using least absolute shrinkage and selection operator(LASSO) analysis.Results: Compared to normal tissues, cytokine activity and interleukin-6 production were highly activated in gastric tumors. Responders to pembrolizumab showed significantly up-regulated expression of IFNγ responserelated genes. Cell type enrichment analysis revealed that Th1 cells were significantly enriched in the tumor microenvironment of responders. Regression analysis indicated that Th1 cells induced IFNγ response more efficiently than other cell types. Using signatures of Th1 cells, stromal cells and IFNγ response, a set of eight genes were identified that effectively predicted the efficacy of immunotherapy treatment and patient prognosis.Conclusions: Th1 cells promote therapeutic efficacy of PD-1 blockade by promoting IFNγ immune response in gastric cancer. The identified biomarkers have the potential to improve the effectiveness of immunotherapy treatment for gastric cancer patients.
基金supported,in part,by the Precision Medical Research Program from Ministry of Science and Technology of China(Grant No.YL 2017YFC0908400)National Science and Technology Major Project for Infectious Disease and Funding(Grant No.YL 17-163-12-ZT-005-095-01)+2 种基金Science and Technology Commission in Ministry of National Defense of China(Grant No.YL 17-163-12-ZT-005-095-01)Xinwei Wang was supported by the intramural research program of the Center for Cancer Research,National Cancer Institute of the United StatesJunfang Ji was supported by the Thousand Young Talents Plan of China,National Natural Science Foundation of China(Grant No.81672905)
文摘Introduction Primary liver cancer, the second most common cause of cancer related death worldwide, presents ethnic, etiological, sex, and geographical diversity2 （Figure 1A）. At the histological level, liver cancer includes two major types： hepatocellular carcinoma （HCC, about 80%） and cholangiocarcinoma （CCA, about 15%）. Many etiological factors contribute to HCC development, such as hepatitis B virus （HBV）, hepatitis C virus （HCV）, aflatoxin B1 （AFB1）, alcohol, and metabolic diseases3. By contrast, the major risk factors for CCA are liver flukes （Opisthorchis viverrini and Clonorchis sinensis） and primary sclerosing cholangitis4,
文摘Recently,an original article tided“A patient-derived glioblastoma organoid model and biobank recapitulates inter-and intra-tumoral heterogeneity”was published in Cell(1),a leading journal of scientific research worldwide.This paper reported that Fadi Jacob and colleagues established an organoids biobank with patient-derived glioblastoma organoids(GBOs),recapitulating the histological features,cellular diversity,gene expression and mutational profiles of their corresponding parental tumors.And functions of these organoids were confirmed both in vitro and in vivo xenograft models.In addition,by modeling targeted drug testing and chimeric antigen receptor T cell(CAR-T)immunotherapy,they demonstrated the application of GBOs in personalized medicine(1)(Figure 1).
基金financially supported by the Guangdong Province Key Research and Development Program (No. 2019B020226002)the National Science and Technology Major Project (No. 2019YFC1315702)。
文摘Objective: Previous investigations of circulating tumor cells(CTCs) have mainly focused on their genomic or transcriptomic features, leaving their epigenetic landscape relatively uncharacterized. Here, we investigated the genome-wide DNA methylome of CTCs with a view to understanding the epigenetic regulatory mechanisms underlying cancer metastasis.Methods: We evaluated single-cell DNA methylome and copy number alteration(CNA) in 196 single cells,including 107 CTCs collected from 17 cancer patients covering six different cancer types. Our single-cell bisulfite sequencing(sc BS-seq) covered on average 11.78% of all Cp G dinucleotides and accurately deduced the CNA patterns at 500 kb resolution.Results: We report distinct subclonal structures and different evolutionary histories of CTCs inferred from CNA and DNA methylation profiles. Furthermore, we demonstrate potential tumor origin classification based on the tissue-specific DNA methylation profiles of CTCs.Conclusions: Our work provides a comprehensive survey of genome-wide DNA methylome in single CTCs and reveals 5-methylcytosine(5-m C) heterogeneity in CTCs, addressing the potential epigenetic regulatory mechanisms underlying cancer metastasis and facilitating the future clinical application of CTCs.
基金supported by a grant from the National Natural Science Foundation of China (Grant No. 31671452)
文摘Introduction As one of the most frequently diagnosed devastating diseases, liver failure is responsible for approximately two million deaths annually worldwide with poor prognosis1. Although liver transplantation has been developed for the most effective treatment for liver failure, it is far from demands for patients due to the shortage of high-quality donor livers and expensive treatment costs. Currently, with the development of cell therapy, cell transplantations including primary human hepatocytes (PHHs), human hepatocyte-like cells (HLCs) and liver organoids are emerging as great potential tools to alleviate this growing burden.
基金supported by National Natural Science Foundation of China (Grant No. 81802813)Scientific Research Seed Fund of Peking University First Hospital (Grant No. 2018SF039)
文摘Immune checkpoint blockade therapy,which targets T cells to enhance the antitumor immune response,has become a promising treatment for many cancer types1,2.Till now,a total of 6 checkpoint inhibitors targeting cytotoxic T lymphocyte antigen-4(CTLA-4)。
文摘Hepatobiliary tumors are of high grade of heterogeneity, which is recognized as a key contributor to drug resistance and poor disease prognosis. However, the intrinsic mechanism between heterogeneity and drug response in hepatobiliary tumor is still largely unknown. Using tumor organoid models, Wang and her colleagues have found that cooperation among distinct subpopulations might be a key mechanism for drug resistance in hepatobiliary tumor.
基金We thank Zichen Xu for assistance in the preparation of the figures.This work was supported by the National Natural Science Foundation of China(81972735,31671452,81970459)Clinical Medicine Plus X-Young Scholars Project of Peking University(71006Y2435).
文摘Primary liver cancer(PLC)is a fatal disease that affects millions of lives worldwide.PLC is the leading cause of cancer-related deaths and the incidence rate is predicted to rise in the coming decades.PLC can be categorized into three major histological subtypes:hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(ICC),and combined HCC-ICC.These subtypes are distinct with respect to epidemiology,clinicopathological features,genetic alterations,and clinical managements,which are thoroughly summarized in this review.The state of treatment strategies for each subtype,including the currently approved drugs and the potential novel therapies,are also discussed.
基金support from Versus Arthritis UK(21327 to D.X.)the National Key R&D Program of China(2021YFC2701800 and 2021YFC2701802 to Y.Z.),the National Natural Science Foundation of China(82241038,81974248 to Y.Z.and 81900751 to X.H.)+5 种基金the International Joint Laboratory Program of National Children’s Medical Center(EK1125180109 to Y.Z.)the Program for Outstanding Medical Academic Leader(2019LJ19 to Y.Z.)the Shanghai Rising-Star Program(22QA1401500 to X.H.)the Shanghai Committee of Science and Technology(21140902400 to Y.Z.,23ZR1407600,21ZR1410000 to F.J.and 20ZR1408300 to X.H.)the Shenzhen Science and Technology Peacock Team Project(KQTD20170331145453160)the National Health Research Institutes,Taiwan,China(EM-109-PP-10).
文摘Cytokine storms are crucial in the development of various inflammatory diseases,including sepsis and autoimmune disorders.The immunosuppressive cytokine INTERLEUKIN(IL)-37 consists of five isoforms(IL-37a-e).We identified IL-37a as a nuclear cytokine for the first time.Compared to IL-37b,IL-37a demonstrated greater efficacy in protecting against Toll-like receptor-induced cytokine hypersecretion and lethal endotoxic shock.The full-length(FL)form of IL-37a and the N-terminal fragment,which is processed by elastase,could translocate into cell nuclei through a distinctive nuclear localization sequence(NLS)/importin nuclear transport pathway.These forms exerted their regulatory effects independent of the IL-1R8 receptor by transcriptionally upregulating the nuclear receptor peroxisome proliferator-activated receptor(PPARγ).This process involved the recruitment of the H3K4 methyltransferase complex WDR5/MLL4/C/EBPβand H3K4me1/2 to the enhancer/promoter of Pparg.The receptor-independent regulatory pathway of the nuclear IL-37a–PPARγaxis and receptor-dependent signaling by secreted IL-37a maintain homeostasis and are potential therapeutic targets for various inflammatory diseases,including sepsis.
