Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing
Abstract 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 comprehensi...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02150-w |
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| author | Ziyi Wang Li Gao Ziheng Jia Liguo Liu Ao Gu Zhaonan Liu Qin Zhu Yichen Zuo Mingjie Yang Shijia Wang Jiyao Ma Jingyun Zhang Shimei Qiu Zhizhen Li Jinghan Wang Dongxi Xiang Fatao Liu Rong Shao Yanjing Li Maolan Li Wu Wei Yingbin Liu |
| author_facet | Ziyi Wang Li Gao Ziheng Jia Liguo Liu Ao Gu Zhaonan Liu Qin Zhu Yichen Zuo Mingjie Yang Shijia Wang Jiyao Ma Jingyun Zhang Shimei Qiu Zhizhen Li Jinghan Wang Dongxi Xiang Fatao Liu Rong Shao Yanjing Li Maolan Li Wu Wei Yingbin Liu |
| author_sort | Ziyi Wang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-7c02a4ae9eb244a19ba7f96d1121a984 |
| institution | OA Journals |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-7c02a4ae9eb244a19ba7f96d1121a9842025-08-20T02:13:07ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-02-0110111310.1038/s41392-025-02150-wFull-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicingZiyi Wang0Li Gao1Ziheng Jia2Liguo Liu3Ao Gu4Zhaonan Liu5Qin Zhu6Yichen Zuo7Mingjie Yang8Shijia Wang9Jiyao Ma10Jingyun Zhang11Shimei Qiu12Zhizhen Li13Jinghan Wang14Dongxi Xiang15Fatao Liu16Rong Shao17Yanjing Li18Maolan Li19Wu Wei20Yingbin Liu21Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineCAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of SciencesDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University school of MedicineCAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of SciencesDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineChangzhou No.2 People Hospital Affiliated to Nanjing Medical UniversityDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Biliary Tract Surgery I, Eastern Hepatobiliary Surgery HospitalDepartment of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary and Pancreatic Surgery, Shanghai East Hospital, School of Medicine, Tongji UniversityShanghai Key Laboratory for Cancer Systems Regulation and Clinical Translation (CSRCT-SHANGHAI), Renji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Key Laboratory for Cancer Systems Regulation and Clinical Translation (CSRCT-SHANGHAI), Renji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University school of MedicineShanghai Key Laboratory for Cancer Systems Regulation and Clinical Translation (CSRCT-SHANGHAI), Renji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineLingang LaboratoryDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1038/s41392-025-02150-w |
| spellingShingle | Ziyi Wang Li Gao Ziheng Jia Liguo Liu Ao Gu Zhaonan Liu Qin Zhu Yichen Zuo Mingjie Yang Shijia Wang Jiyao Ma Jingyun Zhang Shimei Qiu Zhizhen Li Jinghan Wang Dongxi Xiang Fatao Liu Rong Shao Yanjing Li Maolan Li Wu Wei Yingbin Liu Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing Signal Transduction and Targeted Therapy |
| title | Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing |
| title_full | Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing |
| title_fullStr | Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing |
| title_full_unstemmed | Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing |
| title_short | Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing |
| title_sort | full length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by erbb2 alternative splicing |
| url | https://doi.org/10.1038/s41392-025-02150-w |
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