Aberrant RNA alternative splicing in cancer generates varied novel isoforms and protein variants that facilitate cancer progression.Here,we employed the advanced long-read full-length transcriptome sequencing on gallb...Aberrant RNA alternative splicing in cancer generates varied novel isoforms and protein variants that facilitate cancer progression.Here,we employed the advanced long-read full-length transcriptome sequencing on gallbladder normal tissues,tumors,and cell lines to establish a comprehensive full-length gallbladder transcriptomic atlas.It is of note that receptor tyrosine kinases were one of the most dynamic components with highly variable transcript,with Erb-B2 receptor tyrosine kinase 2(ERBB2)as a prime representative.A novel transcript,designated ERBB2 i14e,was identified for encoding a novel functional protein,and its protein expression was elevated in gallbladder cancer and strongly associated with worse prognosis.With the regulation of splicing factors ESRP1/2,ERBB2 i14e was alternatively spliced from intron 14 and the encoded i14e peptide was proved to facilitate the interaction with ERBB3 and downstream signaling activation of AKT.ERBB2 i14e was inducible and its expression attenuated anti-ERBB2 treatment efficacy in tumor xenografts.Further studies with patient derived xenografts models validated that ERBB2 i14e blockage with antisense oligonucleotide enhanced the tumor sensitivity to trastuzumab and its drug conjugates.Overall,this study provides a gallbladder specific long-read transcriptome profile and discovers a novel mechanism of trastuzumab resistance,thus ultimately devising strategies to improve trastuzumab therapy.展开更多
Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer.However,knowledge of the topological rearrangement of genomic hierarchical layer...Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer.However,knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely limited.Here,by taking advantage of in situ Hi-C,RNA-sequencing,and chromatin immunoprecipitation sequencing(ChIP-seq),we investigated structural reorganization and functional changes in chromosomal compartments,topologically associated domains(TADs),and CCCTC binding factor(CTCF)-mediated loops in gallbladder cancer(GBC)tissues and cell lines.We observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression changes.Increased inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal controls.Furthermore,the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial–mesenchymal transition activation were enriched in cancer compared with their control counterparts.Cancer-specific enhancer–promoter loops,which contain multiple transcription factor binding motifs,acted as a central element to regulate aberrant gene expression.Depletion of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene expressions.Collectively,our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.展开更多
Gallbladder cancer(GBC)is rare,but is the most malignant type of biliary tract tumor.Unfortunately,only a small population of cancer patients is acceptable for the surgical resection,the current effective regimen;thus...Gallbladder cancer(GBC)is rare,but is the most malignant type of biliary tract tumor.Unfortunately,only a small population of cancer patients is acceptable for the surgical resection,the current effective regimen;thus,the high mortality rate has been static for decades.To substantially circumvent the stagnant scenario,a number of therapeutic approaches owing to the creation of advanced technologic measures(e.g.,next-generation sequencing,transcriptomics,proteomics)have been intensively innovated,which include targeted therapy,immunotherapy,and nanoparticle-based delivery systems.In the current review,we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC.Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease,ultimately improving the efficacy of treatment.展开更多
Neuroendocrine carcinoma(NEC)of the gallbladder(GB-NEC)is a rare but extremely malignant subtype of gallbladder cancer(GBC).The genetic and molecular signatures of GB-NEC are poorly understood;thus,molecular targeting...Neuroendocrine carcinoma(NEC)of the gallbladder(GB-NEC)is a rare but extremely malignant subtype of gallbladder cancer(GBC).The genetic and molecular signatures of GB-NEC are poorly understood;thus,molecular targeting is currently unavailable.Inthe present study,we applied whole-exome sequencing(WES)technology to detect gene mutations and predicted somatic singlenucleotide variants(SNVs)in 15 cases of GB-NEC and 22 cases of general GBC.in 15 GB-NECs,the C>T mutation was predominantamong the 6 types of SNVs.TP53 showed the highest mutation frequency(73%,11/15).Compared with neuroendocrine carcinomasof other organs,signifcantly mutated genes(SMGs)in GB-NECs were more similar to those in pulmonary large-cell euroendocrinecarcinomas(LCNECs),with drver roles for TP53 and RB1.Iin the COSMIC database of cancer-related genes,211 genes were mutated.Strikingly,RB1(4/15,27%)and NAB2(3/15,20%)mutations were found specifically in GB-NECs;in contrast,mutations in 29 genes,including ERB82 and ERBB3,were identified exclusively in GBC.Mutations in RB1 and NAB2 were significanty related to downregulation of the RB1 and NAB2 proteins,respectively,according to immunohistochemical(IHC)data(p values=0.0453 and0.0303).Clinically actionable genes indicated 23 mutated genes,including ALK,BRCA1,and BRCA2.Iin addition,potential somaticSNVs predicted by ISowN and SomVarlUS constituted 6 primary coSMIC mutation signatures(1,3,30,6,7,and 13)in GB-NEC.Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch,WNT,Hippo,and RTK-RASpathways.In summary,we have systematically identified the mutation landscape of GB-NEC,and these findings may providemechanistic insights into the specifc pathogenesis of this deadly disease.展开更多
基金supported by grants from National Natural Science Foundation of China(No.32130036,82403148,82303937,82073206)Shanghai Shenkang Clinical Technology Innovation Project(No.SHDC12021101)+8 种基金Basic Research Project of Science and Technology Commission of Shanghai Municipality(No.20JC1419100)National Key Research and Development Program of China(No.2021YFE0203300)Science and Technology Innovation Action Plan Technical Standards Project of Science and Technology Commission of Shanghai Municipality(23DZ2202800)Cooperative Research Projects of Shanghai Jiao Tong University(2022LHA13)Major Science and Technology R&D Project of the Science and Technology Department of Jiangxi Province(20213AAG01013)Shanghai Outstanding Academic Leader(23XD1450700),Shanghai Rising-Star Program(23QA1408500)Young Talents Project of Shanghai Municipal Health Commission(2022YQ061)Shanghai Municipal Health Commission health Industry clinical research special project(No.20224Z0014)the Shuguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission(No.20SG14).
文摘Aberrant RNA alternative splicing in cancer generates varied novel isoforms and protein variants that facilitate cancer progression.Here,we employed the advanced long-read full-length transcriptome sequencing on gallbladder normal tissues,tumors,and cell lines to establish a comprehensive full-length gallbladder transcriptomic atlas.It is of note that receptor tyrosine kinases were one of the most dynamic components with highly variable transcript,with Erb-B2 receptor tyrosine kinase 2(ERBB2)as a prime representative.A novel transcript,designated ERBB2 i14e,was identified for encoding a novel functional protein,and its protein expression was elevated in gallbladder cancer and strongly associated with worse prognosis.With the regulation of splicing factors ESRP1/2,ERBB2 i14e was alternatively spliced from intron 14 and the encoded i14e peptide was proved to facilitate the interaction with ERBB3 and downstream signaling activation of AKT.ERBB2 i14e was inducible and its expression attenuated anti-ERBB2 treatment efficacy in tumor xenografts.Further studies with patient derived xenografts models validated that ERBB2 i14e blockage with antisense oligonucleotide enhanced the tumor sensitivity to trastuzumab and its drug conjugates.Overall,this study provides a gallbladder specific long-read transcriptome profile and discovers a novel mechanism of trastuzumab resistance,thus ultimately devising strategies to improve trastuzumab therapy.
基金supported by the National Natural Science Foundation of China(Nos.81874181,81902361,3213000192,and 91940305)the National Science and Technology Major Projects for“Major New Drug Innovation and Development”(No.2019ZX09301-158)+1 种基金the Shanghai Sailing Program(No.19YF1433000)the Open Project Program of State Key Laboratory of Oncogenes and Related Genes(No.KF2120).
文摘Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer.However,knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely limited.Here,by taking advantage of in situ Hi-C,RNA-sequencing,and chromatin immunoprecipitation sequencing(ChIP-seq),we investigated structural reorganization and functional changes in chromosomal compartments,topologically associated domains(TADs),and CCCTC binding factor(CTCF)-mediated loops in gallbladder cancer(GBC)tissues and cell lines.We observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression changes.Increased inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal controls.Furthermore,the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial–mesenchymal transition activation were enriched in cancer compared with their control counterparts.Cancer-specific enhancer–promoter loops,which contain multiple transcription factor binding motifs,acted as a central element to regulate aberrant gene expression.Depletion of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene expressions.Collectively,our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.
基金thank Andy Cumming for providing language assistance.This study was supported in part by Sao Paulo Research Foundation(FAPESP),Grants#2015/09324-9,#15/02200-2,#14/50947-7,and#13/08135-2support also came in part from the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior—Brasil(CAPES),and support also came in part from the National Counsel of Technological and Scientific Development(CNPq).
文摘Gallbladder cancer(GBC)is rare,but is the most malignant type of biliary tract tumor.Unfortunately,only a small population of cancer patients is acceptable for the surgical resection,the current effective regimen;thus,the high mortality rate has been static for decades.To substantially circumvent the stagnant scenario,a number of therapeutic approaches owing to the creation of advanced technologic measures(e.g.,next-generation sequencing,transcriptomics,proteomics)have been intensively innovated,which include targeted therapy,immunotherapy,and nanoparticle-based delivery systems.In the current review,we primarily focus on the targeted therapy capable of specifically inhibiting individual key molecules that govern aberrant signaling cascades in GBC.Global clinical trials of targeted therapy in GBC are updated and may offer great value for novel pathologic and therapeutic insights of this deadly disease,ultimately improving the efficacy of treatment.
基金supported by the National Natural Science Foundation of China(Nos.81902361,31620103910,81874181,91940305,and 81702381)the Shanghai Sailing Program(19YF1433000)+5 种基金the Shanghai Artificial Intelligence Innovation and Development Project(2019-RGZN-01096)the Medical Science and Technology Project of Zhejiang Provincial Health Commission(No.2019334001)the Medical Science and Technology Program of Ningbo(No.2019Y06)the Natural Science Foundation of Ningbo(No.2019A610208)the Shanghai Key Laboratory of Biliary Tract Disease Research Foundation(17DZ2260200)appreciate the support from the Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine(JYKCGZS04).
文摘Neuroendocrine carcinoma(NEC)of the gallbladder(GB-NEC)is a rare but extremely malignant subtype of gallbladder cancer(GBC).The genetic and molecular signatures of GB-NEC are poorly understood;thus,molecular targeting is currently unavailable.Inthe present study,we applied whole-exome sequencing(WES)technology to detect gene mutations and predicted somatic singlenucleotide variants(SNVs)in 15 cases of GB-NEC and 22 cases of general GBC.in 15 GB-NECs,the C>T mutation was predominantamong the 6 types of SNVs.TP53 showed the highest mutation frequency(73%,11/15).Compared with neuroendocrine carcinomasof other organs,signifcantly mutated genes(SMGs)in GB-NECs were more similar to those in pulmonary large-cell euroendocrinecarcinomas(LCNECs),with drver roles for TP53 and RB1.Iin the COSMIC database of cancer-related genes,211 genes were mutated.Strikingly,RB1(4/15,27%)and NAB2(3/15,20%)mutations were found specifically in GB-NECs;in contrast,mutations in 29 genes,including ERB82 and ERBB3,were identified exclusively in GBC.Mutations in RB1 and NAB2 were significanty related to downregulation of the RB1 and NAB2 proteins,respectively,according to immunohistochemical(IHC)data(p values=0.0453 and0.0303).Clinically actionable genes indicated 23 mutated genes,including ALK,BRCA1,and BRCA2.Iin addition,potential somaticSNVs predicted by ISowN and SomVarlUS constituted 6 primary coSMIC mutation signatures(1,3,30,6,7,and 13)in GB-NEC.Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch,WNT,Hippo,and RTK-RASpathways.In summary,we have systematically identified the mutation landscape of GB-NEC,and these findings may providemechanistic insights into the specifc pathogenesis of this deadly disease.
