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
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.
