Hepatocellular carcinoma(HCC)is the fifth most widespread cancer responsible for one fourth of cancer-related deaths globally.Persistent infection with hepatitis B virus(HBV)remains the main cause of HCC summing up to...Hepatocellular carcinoma(HCC)is the fifth most widespread cancer responsible for one fourth of cancer-related deaths globally.Persistent infection with hepatitis B virus(HBV)remains the main cause of HCC summing up to 50%of its causative etiology.Our recent studies,supported by findings from others,uncovered that HBV and its close relative woodchuck hepatitis virus(WHV)integrate into hepatocyte genome almost immediately,hence in minutes after infection.Retrotransposons and genes with translocation potential were found to be frequent sites of HBV insertions,suggesting a mechanism of HBV DNA spread across liver genome from the earliest stages after virus invasion.Many other genes were identified as the sites of early hepadnavirus merges in human hepatocyte-like lines infected de novo with HBV and in natural woodchuck WHV infection model.It was uncovered that head-to-tail joins(HTJs)prevail among the earliest virus-host fusions,implying their formation via the non-homologous-end-joining(NHEJ)pathway.Overlapping homologous junctions resulting from the micro-homology-mediated-overlapping-joining(MHMOJ)were rarely detected.Formation of the initial HTJs coincided with strong induction of reactive oxygen species(ROS)and transient appearance of inducible nitric oxide(iNOS).This was accompanied by cell DNA damage and activation of the poly(ADP-ribose)polymerase 1(PARP1)-mediated host DNA repair machinery,which may explain predominant HTJ format of the first virushost fusions.Identification of initial integration sites and resulting alterations in hepatocyte phenotype may pave a way to discovery of reliable markers of HBV-triggered HCC,including HCC resulting from occult HBV infection.Our research strongly argues that HBV is an ultimate human carcinogen capable of initiation of a pro-oncogenic process immediately after first contact with a susceptible host.展开更多
Oncovirus infection is crucial in human malignancies.Certain oncoviruses can lead to structural variations in the human genome known as viral genomic integration,which can contribute to tumorigenesis.Existing viral in...Oncovirus infection is crucial in human malignancies.Certain oncoviruses can lead to structural variations in the human genome known as viral genomic integration,which can contribute to tumorigenesis.Existing viral integration detection tools differ in their underlying algorithms pinpointing different aspects or features of viral integration phenomenon.We discuss about major procedures in performing viral integration detection.More importantly,we provide a technical update on Virus-Clip to facilitate its usage on the latest human genome builds(hg19 and hg38)and the adoption of multi-thread mode for faster initial read alignment.By comparing the execution of Virus-Clip using single-thread and multi-thread modes of read alignment on targeted-panel sequencing data of HBV-associated hepatocellular carcinoma patients,we demonstrate the marked improvement of multi-thread mode in terms of significantly reduced execution time,while there is negligible difference in memory usage.Taken together,with the current update of Virus-Clip,it will continue supporting the in silico detection of oncoviral integration for better understanding of various human malignancies.展开更多
Ten years after the initial generation of induced pluripotent stem cells(hiPSCs)from human tissues,their potential is no longer questioned,with over 15000 publications listed on PubMed,covering various fields of resea...Ten years after the initial generation of induced pluripotent stem cells(hiPSCs)from human tissues,their potential is no longer questioned,with over 15000 publications listed on PubMed,covering various fields of research;including disease modeling,cell therapy strategies,pharmacology/toxicology screening and 3D organoid systems.However,despite evidences that the presence of mutations in hiPSCs should be a concern,publications addressing genomic integrity of these cells represent less than 1%of the literature.After a first overview of the mutation types currently reported in hiPSCs,including karyotype abnormalities,copy number variations,single point mutation as well as uniparental disomy,this review will discuss the impact of reprogramming parameters such as starting cell type and reprogramming method on the maintenance of the cellular genomic integrity.Then,a specific focus will be placed on culture conditions and subsequent differentiation protocols and how their may also trigger genomic aberrations within the cell population of interest.Finally,in a last section,the impact of genomic alterations on the possible usages of hiPSCs and their derivatives will also be exemplified and discussed.We will also discuss which techniques or combination of techniques should be used to screen for genomic abnormalities with a particular focus on the necessary quality controls and the potential alternatives.展开更多
We propose a novel conditional graphical model -- spaceMap -- to construct gene regulatory networks from multiple types of high dimensional omic profiles. A motivating application is to characterize the perturbation o...We propose a novel conditional graphical model -- spaceMap -- to construct gene regulatory networks from multiple types of high dimensional omic profiles. A motivating application is to characterize the perturbation of DNA copy number alterations （CNAs） on downstream protein levels in tumors. Through a penalized multivariate regression framework, spaceMap jointly models high dimensional protein levels as responses and high dimensional CNAs as predictors. In this setup, spaceMap infers an undirected network among proteins together with a directed network encoding how CNAs perturb the protein network, spaceMap can be applied to learn other types of regulatory relationships from high dimensional molecular profiles, especially those exhibiting hub structures. Simulation studies show spaceMap has greater power in detecting regulatory relationships over competing methods. Additionally, spaceMap includes a network analysis toolkit for biological interpretation of inferred networks. We applies spaceMap to the CNAs, gene expression and proteomics data sets from CPTAC-TCGA breast （n = 77） and ovarian （n = 174） cancer studies. Each cancer exhibits disruption of＇ion transmembrane transport＇ and ＇regulation from RNA polymerase lI promoter＇ by CNA events unique to each cancer. Moreover, using protein levels as a response yields a more functionally-enriched network than using RNA expressions in both cancer types. The network results also help to pinpoint crucial cancer genes and provide insights on the functional consequences of important CNA in breast and ovarian cancers.展开更多
Yarrowia lipolytica is a promising host for producing valuable chemicals owing to its robustness and metabolic versatility.Efficient genome editing tools are essential for advancing its biotechnological applications.A...Yarrowia lipolytica is a promising host for producing valuable chemicals owing to its robustness and metabolic versatility.Efficient genome editing tools are essential for advancing its biotechnological applications.Although CRISPR/Cas9 technology has been applied in Y.lipolytica,achieving a consistently high editing performance re-mains challenging owing to the low homologous recombination efficiency and variability in system components.In this study,we optimized CRISPR/Cas9-mediated genome editing in Y.lipolytica to enhance its editing effi-ciency.Using the RNA polymerase III promoter SCR1-tRNA for sgRNA expression,we achieved a gene disruption efficiency of 92.5%.The tRNA-sgRNA architecture enabled a dual gene disruption efficiency of 57.5%.KU70 deletion in the Cas9 system increased the integration efficiency to 92.5%,and Rad52 and Sae2 overexpression boosted homologous recombination.The introduction of Cas9D147Y,P411T(iCas9)enhanced the efficiency of both gene disruption and genome integration.This study provides a powerful tool for efficient gene editing in Y.lipolytica,which will accelerate the construction of yeast cell factories.展开更多
Chemo-/radioresistance of malignant tumors hampers cancer control and increases patient mortality.Efficient repair of damaged DNA is critical for the maintenance of genomic integrity and fidelity of genetic informatio...Chemo-/radioresistance of malignant tumors hampers cancer control and increases patient mortality.Efficient repair of damaged DNA is critical for the maintenance of genomic integrity and fidelity of genetic information.In reverse,increased DNA repair capability in cancer cells contributes to chemo-/radioresistance of malignant tumors.DNA double-strand break(DSB)is the most serious DNA damage and is also the principal molecular basis of radiotherapy.Upon DNA damage,the Ku80 is recruited and forms a critical DNA-PK complex at the DSB sites with Ku70 and the catalytic subunit(DNA-PKcs)to initiate DNA repair.How DNA-PK is assembled and activated is not fully understood.Based on the identification of radiation-reduced Ku80 K568 crotonylation through quantitative global lysine crotonylome analysis,we reveal that Ku80 K568 is crotonylated by p300-CBP-associated factor(PCAF).Upon DNA damage,the K568cr is decrotonylated by HDAC8(Histone deacetylase 8).Decrotonylation of K568cr empties this site for the subsequent SUMOylation of Ku80 by CBX4.The conversion of Ku80 from K568 crotonylation to SUMOylation facilitates the assembly of DNA-PK complex and autophosphorylation of DNA-PKcs S2056,consequently activating the DSB repair.Moreover,mutation disrupting the post-translational modification(PTM)of Ku80 K568 site sensitizes cancer cells to radiotherapy in tumorbearing nude mice models.This study elucidates the conversion model between two different forms of PTMs in the regulation of DNA-PK complex assembly and DSB repair,highlighting this model’s potential in controlling chemo-/radioresistance of malignant tumors,as well as expands the atlas of therapeutic targets.展开更多
The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the pre...The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.展开更多
Genomic studies of cancer cell alterations,such as mutations,copy number variations(CNVs),and translocations,greatly promote our understanding of the genesis and development of cancers.However,the 3D genome architectu...Genomic studies of cancer cell alterations,such as mutations,copy number variations(CNVs),and translocations,greatly promote our understanding of the genesis and development of cancers.However,the 3D genome architecture of cancers remains less studied due to the complexity of cancer genomes and technical difficulties.To explore the 3D genome structure in clinical lung cancer,we performed Hi-C experiments using paired normal and tumor cells harvested from patients with lung cancer,combining with RNA sequenceing analysis.We demonstrated the feasibility of studying 3D genome of clinical lung cancer samples with a small number of cells(1×10^(4)),compared the genome architecture between clinical samples and cell lines of lung cancer,and identified conserved and changed spatial chromatin structures between normal and cancer samples.We also showed that Hi-C data can be used to infer CNVs and point mutations in cancer.By integrating those different types of cancer alterations,we showed significant associations between CNVs,3D genome,and gene expression.We propose that 3D genome mediates the effects of cancer genomic alterations on gene expression through altering regulatory chromatin structures.Our study highlights the importance of analyzing 3D genomes of clinical cancer samples in addition to cancer cell lines and provides an integrative genomic analysis pipeline for future larger-scale studies in lung cancer and other cancers.展开更多
Ribosomal proteins （RPs）, the essential components of the ribosome, are a family of RNA-binding proteins, which play prime roles in ribosome biogenesis and protein translation. Recent studies revealed that RPs have ...Ribosomal proteins （RPs）, the essential components of the ribosome, are a family of RNA-binding proteins, which play prime roles in ribosome biogenesis and protein translation. Recent studies revealed that RPs have additional extra-ribosomal func- tions, independent of protein biosynthesis, in regulation of diverse cellular processes. Here, we review recent advances in our understanding of how RPs regulate apoptosis, cell cycle arrest, cell proliferation, neoplastic transformation, cell migration and invasion, and tumorigenesis through both MDM2/p53-dependent and p53-independent mechanisms. We also discuss the roles of RPs in the maintenance of genome integrity via modulating DNA damage response and repair. We further discuss mutations or deletions at the somatic or gennline levels of some RPs in human cancers as well as in patients of Diamond-Blackfan ane- mia and 5q- syndrome with high susceptibility to cancer development. Moreover, we discuss the potential clinical application, based upon abnormal levels of RPs, in biomarker development for early diagnosis and/or prognosis of certain human cancers. Finally, we discuss the pressing issues in the field as future perspectives for better understanding the roles of RPs in human cancers to eventually benefit human health.展开更多
Publicly-accessible resources have promoted the advance of scientific discovery. The era of genomics and big data has brought the need for collaboration and data sharing in order to make effective use of this new know...Publicly-accessible resources have promoted the advance of scientific discovery. The era of genomics and big data has brought the need for collaboration and data sharing in order to make effective use of this new knowledge. Here, we describe the web resources for cancer genomics research and rate them on the basis of the diversity of cancer types, sample size, omics data comprehensiveness, and user experience. The resources reviewed include data repository and analysis tools; and we hope such introduction will promote the awareness and facilitate the usage of these resources in the cancer research community.展开更多
＂Omics＂ is a new research field of integrative systems biology and bioinformatics.In the post genomic era,the core scientific problem is to study the relationship between different ＂omics＂ and functions based on b...＂Omics＂ is a new research field of integrative systems biology and bioinformatics.In the post genomic era,the core scientific problem is to study the relationship between different ＂omics＂ and functions based on bioinformatics.How to apply the omics method and technology to understand the complexity of traditional Chinese medicines（TCM）is one of the hot spots in the recent decade in China.展开更多
Epithelial and stromal tissues are components of the tumor microenvironment and play a major role in tumor initiation and progression.Distinguishing stroma from epithelial tissues is critically important for spatial c...Epithelial and stromal tissues are components of the tumor microenvironment and play a major role in tumor initiation and progression.Distinguishing stroma from epithelial tissues is critically important for spatial characterization of the tumor microenvironment.Here,we propose BrcaSeg,an image analysis pipeline based on a convolutional neural network(CNN)model to classify epithelial and stromal regions in whole-slide hematoxylin and eosin(H&E)stained histopathological images.The CNN model is trained using well-annotated breast cancer tissue microarrays and validated with images from The Cancer Genome Atlas(TCGA)Program.BrcaSeg achieves a classification accuracy of 91.02%,which outperforms other state-of-the-art methods.Using this model,we generate pixel-level epithelial/stromal tissue maps for 1000 TCGA breast cancer slide images that are paired with gene expression data.We subsequently estimate the epithelial and stromal ratios and perform correlation analysis to model the relationship between gene expression and tissue ratios.Gene Ontology(GO)enrichment analyses of genes that are highly correlated with tissue ratios suggest that the same tissue is associated with similar biological processes in different breast cancer subtypes,whereas each subtype also has its own idiosyncratic biological processes governing the development of these tissues.Taken all together,our approach can lead to new insights in exploring relationships between image-based phenotypes and their underlying genomic events and biological processes for all types of solid tumors.BrcaSeg can be accessed at https://github.com/Serian1992/ImgBio.展开更多
基金supported by an operating grant(PIN 22346)from the Cancer Research Society Inc.,Canada and the Environmental Cancer Fund-Read for the Cure,Canada and in part by an operating grant(PJT-153001)from the Canadian Institutes of Health Research awarded to Michalak TI.
文摘Hepatocellular carcinoma(HCC)is the fifth most widespread cancer responsible for one fourth of cancer-related deaths globally.Persistent infection with hepatitis B virus(HBV)remains the main cause of HCC summing up to 50%of its causative etiology.Our recent studies,supported by findings from others,uncovered that HBV and its close relative woodchuck hepatitis virus(WHV)integrate into hepatocyte genome almost immediately,hence in minutes after infection.Retrotransposons and genes with translocation potential were found to be frequent sites of HBV insertions,suggesting a mechanism of HBV DNA spread across liver genome from the earliest stages after virus invasion.Many other genes were identified as the sites of early hepadnavirus merges in human hepatocyte-like lines infected de novo with HBV and in natural woodchuck WHV infection model.It was uncovered that head-to-tail joins(HTJs)prevail among the earliest virus-host fusions,implying their formation via the non-homologous-end-joining(NHEJ)pathway.Overlapping homologous junctions resulting from the micro-homology-mediated-overlapping-joining(MHMOJ)were rarely detected.Formation of the initial HTJs coincided with strong induction of reactive oxygen species(ROS)and transient appearance of inducible nitric oxide(iNOS).This was accompanied by cell DNA damage and activation of the poly(ADP-ribose)polymerase 1(PARP1)-mediated host DNA repair machinery,which may explain predominant HTJ format of the first virushost fusions.Identification of initial integration sites and resulting alterations in hepatocyte phenotype may pave a way to discovery of reliable markers of HBV-triggered HCC,including HCC resulting from occult HBV infection.Our research strongly argues that HBV is an ultimate human carcinogen capable of initiation of a pro-oncogenic process immediately after first contact with a susceptible host.
基金the National Natural Science Foundation of China(81872222)Hong Kong Research Grants Council Theme-based Research Scheme(T12-704/16-R)。
文摘Oncovirus infection is crucial in human malignancies.Certain oncoviruses can lead to structural variations in the human genome known as viral genomic integration,which can contribute to tumorigenesis.Existing viral integration detection tools differ in their underlying algorithms pinpointing different aspects or features of viral integration phenomenon.We discuss about major procedures in performing viral integration detection.More importantly,we provide a technical update on Virus-Clip to facilitate its usage on the latest human genome builds(hg19 and hg38)and the adoption of multi-thread mode for faster initial read alignment.By comparing the execution of Virus-Clip using single-thread and multi-thread modes of read alignment on targeted-panel sequencing data of HBV-associated hepatocellular carcinoma patients,we demonstrate the marked improvement of multi-thread mode in terms of significantly reduced execution time,while there is negligible difference in memory usage.Taken together,with the current update of Virus-Clip,it will continue supporting the in silico detection of oncoviral integration for better understanding of various human malignancies.
文摘Ten years after the initial generation of induced pluripotent stem cells(hiPSCs)from human tissues,their potential is no longer questioned,with over 15000 publications listed on PubMed,covering various fields of research;including disease modeling,cell therapy strategies,pharmacology/toxicology screening and 3D organoid systems.However,despite evidences that the presence of mutations in hiPSCs should be a concern,publications addressing genomic integrity of these cells represent less than 1%of the literature.After a first overview of the mutation types currently reported in hiPSCs,including karyotype abnormalities,copy number variations,single point mutation as well as uniparental disomy,this review will discuss the impact of reprogramming parameters such as starting cell type and reprogramming method on the maintenance of the cellular genomic integrity.Then,a specific focus will be placed on culture conditions and subsequent differentiation protocols and how their may also trigger genomic aberrations within the cell population of interest.Finally,in a last section,the impact of genomic alterations on the possible usages of hiPSCs and their derivatives will also be exemplified and discussed.We will also discuss which techniques or combination of techniques should be used to screen for genomic abnormalities with a particular focus on the necessary quality controls and the potential alternatives.
基金supported by the Floyd and Mary Schwall Fellowship in Medical Research and grants NIH R01-GM082802, R01-GM108711, R01-CA189532 and NSF DMS-1148643partly supported by grant U24 CA 210093, from the National Cancer Institute Clinical Proteomic Tumor Analysis Consortium (CPTAC)
文摘We propose a novel conditional graphical model -- spaceMap -- to construct gene regulatory networks from multiple types of high dimensional omic profiles. A motivating application is to characterize the perturbation of DNA copy number alterations （CNAs） on downstream protein levels in tumors. Through a penalized multivariate regression framework, spaceMap jointly models high dimensional protein levels as responses and high dimensional CNAs as predictors. In this setup, spaceMap infers an undirected network among proteins together with a directed network encoding how CNAs perturb the protein network, spaceMap can be applied to learn other types of regulatory relationships from high dimensional molecular profiles, especially those exhibiting hub structures. Simulation studies show spaceMap has greater power in detecting regulatory relationships over competing methods. Additionally, spaceMap includes a network analysis toolkit for biological interpretation of inferred networks. We applies spaceMap to the CNAs, gene expression and proteomics data sets from CPTAC-TCGA breast （n = 77） and ovarian （n = 174） cancer studies. Each cancer exhibits disruption of＇ion transmembrane transport＇ and ＇regulation from RNA polymerase lI promoter＇ by CNA events unique to each cancer. Moreover, using protein levels as a response yields a more functionally-enriched network than using RNA expressions in both cancer types. The network results also help to pinpoint crucial cancer genes and provide insights on the functional consequences of important CNA in breast and ovarian cancers.
基金supported by the National Natural Science Founda-tion of China(U23A20268)the National Natural Science Foundation of Shandong Province(ZR2022ZD24)the Taishan Scholar Project of Shandong Province(tsqn202312061).
文摘Yarrowia lipolytica is a promising host for producing valuable chemicals owing to its robustness and metabolic versatility.Efficient genome editing tools are essential for advancing its biotechnological applications.Although CRISPR/Cas9 technology has been applied in Y.lipolytica,achieving a consistently high editing performance re-mains challenging owing to the low homologous recombination efficiency and variability in system components.In this study,we optimized CRISPR/Cas9-mediated genome editing in Y.lipolytica to enhance its editing effi-ciency.Using the RNA polymerase III promoter SCR1-tRNA for sgRNA expression,we achieved a gene disruption efficiency of 92.5%.The tRNA-sgRNA architecture enabled a dual gene disruption efficiency of 57.5%.KU70 deletion in the Cas9 system increased the integration efficiency to 92.5%,and Rad52 and Sae2 overexpression boosted homologous recombination.The introduction of Cas9D147Y,P411T(iCas9)enhanced the efficiency of both gene disruption and genome integration.This study provides a powerful tool for efficient gene editing in Y.lipolytica,which will accelerate the construction of yeast cell factories.
基金supported by the National Natural Science Foundation of China(No.82230108,32171238,82173466,and 82273581).
文摘Chemo-/radioresistance of malignant tumors hampers cancer control and increases patient mortality.Efficient repair of damaged DNA is critical for the maintenance of genomic integrity and fidelity of genetic information.In reverse,increased DNA repair capability in cancer cells contributes to chemo-/radioresistance of malignant tumors.DNA double-strand break(DSB)is the most serious DNA damage and is also the principal molecular basis of radiotherapy.Upon DNA damage,the Ku80 is recruited and forms a critical DNA-PK complex at the DSB sites with Ku70 and the catalytic subunit(DNA-PKcs)to initiate DNA repair.How DNA-PK is assembled and activated is not fully understood.Based on the identification of radiation-reduced Ku80 K568 crotonylation through quantitative global lysine crotonylome analysis,we reveal that Ku80 K568 is crotonylated by p300-CBP-associated factor(PCAF).Upon DNA damage,the K568cr is decrotonylated by HDAC8(Histone deacetylase 8).Decrotonylation of K568cr empties this site for the subsequent SUMOylation of Ku80 by CBX4.The conversion of Ku80 from K568 crotonylation to SUMOylation facilitates the assembly of DNA-PK complex and autophosphorylation of DNA-PKcs S2056,consequently activating the DSB repair.Moreover,mutation disrupting the post-translational modification(PTM)of Ku80 K568 site sensitizes cancer cells to radiotherapy in tumorbearing nude mice models.This study elucidates the conversion model between two different forms of PTMs in the regulation of DNA-PK complex assembly and DSB repair,highlighting this model’s potential in controlling chemo-/radioresistance of malignant tumors,as well as expands the atlas of therapeutic targets.
基金supported the Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional“Una manera de hacer Europa”to RMM(PI 19/01884 and PI22/01506)by the Government of Navarra(34/2021)/50%FEDER 2014-2020 and by the Foundation AECC(PRYES211377MART)+7 种基金funded by Cancer Research Thematic Network of the Instituto de Salud Carlos III(RTICC RD12/0036/0066)SAF2015-71606R,RTI2018-094507B-100 financed by MCIN/AEI/10.13039/501100011033/and by FEDER“Una manera de hacer Europa”MICIU PID2021-1226380B-100 and PID2024-156335OB-100supported by FIS(PI22/01253)supported by the Foundation for Applied Medical Research(FIMA)and CIBERONC(CB16/12/00443)funded by the Government of Navarra of the I+D 2022-25,GEMA(GRANATE:Grupo de Radioterapia Avanzada de Navarra,0011-1411-2022-000066 and 0011-1411-2022-000073)supported by a Project PID2023-152755OB-I00 funded by MICIU/AEI/10.13039/501100011033 and by FEDER,EU.K.Vsupported by an Investigator grant from AECC.F.L.and S.V.report research funding from Roche.F.L.and R.M.-M.report consulting fees from Ellipses Life.No potential conflicts of interest were disclosed by the other authors.
文摘The ATP-hydrolytic ectoenzyme ENPP1 has been implicated in the metastasis and recurrence in triple-negative breast cancer(TNBC),primarily by contributing to tumor cell survival and treatment resistance.However,the precise mechanisms remain unclear.In a model of local recurrence(LR),circulating tumor cells(CTC)engrafting in the post-resection tumor bed developed a radioresistant phenotype linked to an ENPP1+-gene signature which was also identified in TNBC patients,suggesting ENPP1´s role in genome integrity.Blockade of ENPP1 using a permeable ENPP1 inhibitor(AVA-NP-695)reduced radioresistance,mechanistically attributed to decreased homologous recombination(HR)resulting in persistent DNA damage,as evidenced by enhanced tail moment and sustainedγH2AX formation.This impaired DNA damage repair(DDR)sensitized tumor cells to ionizing radiation(IR).Notably,several DDR inhibitors(i)(including PARPi and ATMi)showed the highest synergy score in a targeted pharmacological screening.In vivo,dual ENPP1/ATM inhibition heightened radiosensitivity,compromised tumor cell survival and enhanced STINGTBK1 signaling by preventing ENPP1-mediated cGAMP hydrolysis.This resulted in robust innate and long-lasting adaptive antitumor immune memory responses,leading to significant tumor regression.Remarkably,combined treatment post-IR reduced spontaneous metastasis and local recurrence,and induced abscopal effects that impacted distant tumor spread in orthotopic tumor models.Thus,these findings position ENPP1 as a critical link between genome integrity and immunosuppression,offering promising translational opportunities for treating local or distant dissemination in TNBC.
基金supported by the National Natural Science Foundation of China(Grant No.31871266)the National Key R&D Program of China(Grant No.2016YFA0100103)+1 种基金the National Natural Science Foundation of China Key Research Grant(Grant No.71532001)supported by funding from Shenzhen Municipal Government of China(Grant No.DRC-SZ[2016]884)。
文摘Genomic studies of cancer cell alterations,such as mutations,copy number variations(CNVs),and translocations,greatly promote our understanding of the genesis and development of cancers.However,the 3D genome architecture of cancers remains less studied due to the complexity of cancer genomes and technical difficulties.To explore the 3D genome structure in clinical lung cancer,we performed Hi-C experiments using paired normal and tumor cells harvested from patients with lung cancer,combining with RNA sequenceing analysis.We demonstrated the feasibility of studying 3D genome of clinical lung cancer samples with a small number of cells(1×10^(4)),compared the genome architecture between clinical samples and cell lines of lung cancer,and identified conserved and changed spatial chromatin structures between normal and cancer samples.We also showed that Hi-C data can be used to infer CNVs and point mutations in cancer.By integrating those different types of cancer alterations,we showed significant associations between CNVs,3D genome,and gene expression.We propose that 3D genome mediates the effects of cancer genomic alterations on gene expression through altering regulatory chromatin structures.Our study highlights the importance of analyzing 3D genomes of clinical cancer samples in addition to cancer cell lines and provides an integrative genomic analysis pipeline for future larger-scale studies in lung cancer and other cancers.
基金supported by the National Natural Science Foundation of China (81572708, 31501129 to Xiufang Xiong 81572718 to Yi Sun)
文摘Ribosomal proteins （RPs）, the essential components of the ribosome, are a family of RNA-binding proteins, which play prime roles in ribosome biogenesis and protein translation. Recent studies revealed that RPs have additional extra-ribosomal func- tions, independent of protein biosynthesis, in regulation of diverse cellular processes. Here, we review recent advances in our understanding of how RPs regulate apoptosis, cell cycle arrest, cell proliferation, neoplastic transformation, cell migration and invasion, and tumorigenesis through both MDM2/p53-dependent and p53-independent mechanisms. We also discuss the roles of RPs in the maintenance of genome integrity via modulating DNA damage response and repair. We further discuss mutations or deletions at the somatic or gennline levels of some RPs in human cancers as well as in patients of Diamond-Blackfan ane- mia and 5q- syndrome with high susceptibility to cancer development. Moreover, we discuss the potential clinical application, based upon abnormal levels of RPs, in biomarker development for early diagnosis and/or prognosis of certain human cancers. Finally, we discuss the pressing issues in the field as future perspectives for better understanding the roles of RPs in human cancers to eventually benefit human health.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences,Stem Cell and Regenerative Medicine Research(Grant No.XDA01040405)the National High-tech R&D Program of China(863Program,2012AA022502)+1 种基金the National‘‘Twelfth FiveYear’’Plan for Science&Technology Support of China(2013BAI01B09) awarded to XFthe National Natural Science Foundation of China(Grant No.31471236)awarded to YL
文摘Publicly-accessible resources have promoted the advance of scientific discovery. The era of genomics and big data has brought the need for collaboration and data sharing in order to make effective use of this new knowledge. Here, we describe the web resources for cancer genomics research and rate them on the basis of the diversity of cancer types, sample size, omics data comprehensiveness, and user experience. The resources reviewed include data repository and analysis tools; and we hope such introduction will promote the awareness and facilitate the usage of these resources in the cancer research community.
文摘＂Omics＂ is a new research field of integrative systems biology and bioinformatics.In the post genomic era,the core scientific problem is to study the relationship between different ＂omics＂ and functions based on bioinformatics.How to apply the omics method and technology to understand the complexity of traditional Chinese medicines（TCM）is one of the hot spots in the recent decade in China.
基金supported by Indiana University Precision Health Initiative to KH and JZthe NSFC-Guangdong Joint Fund of China (Grant No. U1501256) to QFShenzhen Peacock Plan (Grant No. KQTD2016053112051497) to XZ and ND.
文摘Epithelial and stromal tissues are components of the tumor microenvironment and play a major role in tumor initiation and progression.Distinguishing stroma from epithelial tissues is critically important for spatial characterization of the tumor microenvironment.Here,we propose BrcaSeg,an image analysis pipeline based on a convolutional neural network(CNN)model to classify epithelial and stromal regions in whole-slide hematoxylin and eosin(H&E)stained histopathological images.The CNN model is trained using well-annotated breast cancer tissue microarrays and validated with images from The Cancer Genome Atlas(TCGA)Program.BrcaSeg achieves a classification accuracy of 91.02%,which outperforms other state-of-the-art methods.Using this model,we generate pixel-level epithelial/stromal tissue maps for 1000 TCGA breast cancer slide images that are paired with gene expression data.We subsequently estimate the epithelial and stromal ratios and perform correlation analysis to model the relationship between gene expression and tissue ratios.Gene Ontology(GO)enrichment analyses of genes that are highly correlated with tissue ratios suggest that the same tissue is associated with similar biological processes in different breast cancer subtypes,whereas each subtype also has its own idiosyncratic biological processes governing the development of these tissues.Taken all together,our approach can lead to new insights in exploring relationships between image-based phenotypes and their underlying genomic events and biological processes for all types of solid tumors.BrcaSeg can be accessed at https://github.com/Serian1992/ImgBio.
