Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective treatment strategies. There is an urgent need for the development of new strategies for PDAC therapy. The genetic and phenotypic heterogeneity of PDAC cancer cell populations poses further challen...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-03-01
|
| Series: | Oncogenesis |
| Online Access: | https://doi.org/10.1038/s41389-021-00311-4 |
| _version_ | 1819163873906786304 |
|---|---|
| author | Li-Peng Hu Kai-Xia Zhou Yan-Miao Huo De-Jun Liu Qing Li Min-Wei Yang Pei-Qi Huang Chun-Jie Xu Guang-Ang Tian Lin-Li Yao Xue-Li Zhang Ya-Hui Wang Jun Li Zhi-Gang Zhang Shu-Heng Jiang Xin Xing Xu Wang Wei-Ting Qin Qin Yang |
| author_facet | Li-Peng Hu Kai-Xia Zhou Yan-Miao Huo De-Jun Liu Qing Li Min-Wei Yang Pei-Qi Huang Chun-Jie Xu Guang-Ang Tian Lin-Li Yao Xue-Li Zhang Ya-Hui Wang Jun Li Zhi-Gang Zhang Shu-Heng Jiang Xin Xing Xu Wang Wei-Ting Qin Qin Yang |
| author_sort | Li-Peng Hu |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective treatment strategies. There is an urgent need for the development of new strategies for PDAC therapy. The genetic and phenotypic heterogeneity of PDAC cancer cell populations poses further challenges in the clinical management of PDAC. In this study, we performed single-cell RNA sequencing to characterize PDAC tumors from KPC mice. Functional studies and clinical analysis showed that PDAC cluster 2 cells with highly Hsp90 expression is much more aggressive than the other clusters. Genetic and pharmacologic inhibition of Hsp90 impaired tumor cell growth both in vitro and in vivo. Further mechanistic study revealed that HSP90 inhibition disrupted the interaction between HSP90 and OPA1, leading to a reduction in mitochondrial cristae amount and mitochondrial energy production. Collectively, our study reveals that HSP90 might be a potential therapeutic target for PDAC. |
| first_indexed | 2024-12-22T17:51:03Z |
| format | Article |
| id | doaj.art-b390422c94f543ee8980cc467d58e1b0 |
| institution | Directory Open Access Journal |
| issn | 2157-9024 |
| language | English |
| last_indexed | 2024-12-22T17:51:03Z |
| publishDate | 2021-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Oncogenesis |
| spelling | doaj.art-b390422c94f543ee8980cc467d58e1b02022-12-21T18:18:11ZengNature Publishing GroupOncogenesis2157-90242021-03-0110311110.1038/s41389-021-00311-4Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergeticsLi-Peng Hu0Kai-Xia Zhou1Yan-Miao Huo2De-Jun Liu3Qing Li4Min-Wei Yang5Pei-Qi Huang6Chun-Jie Xu7Guang-Ang Tian8Lin-Li Yao9Xue-Li Zhang10Ya-Hui Wang11Jun Li12Zhi-Gang Zhang13Shu-Heng Jiang14Xin Xing15Xu Wang16Wei-Ting Qin17Qin Yang18State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityDepartment of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghai Fengxian District Central HospitalDepartment of Radiation Oncology, Institute of Oncology, Affiliated Hospital of Jiangsu UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong UniversityAbstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective treatment strategies. There is an urgent need for the development of new strategies for PDAC therapy. The genetic and phenotypic heterogeneity of PDAC cancer cell populations poses further challenges in the clinical management of PDAC. In this study, we performed single-cell RNA sequencing to characterize PDAC tumors from KPC mice. Functional studies and clinical analysis showed that PDAC cluster 2 cells with highly Hsp90 expression is much more aggressive than the other clusters. Genetic and pharmacologic inhibition of Hsp90 impaired tumor cell growth both in vitro and in vivo. Further mechanistic study revealed that HSP90 inhibition disrupted the interaction between HSP90 and OPA1, leading to a reduction in mitochondrial cristae amount and mitochondrial energy production. Collectively, our study reveals that HSP90 might be a potential therapeutic target for PDAC.https://doi.org/10.1038/s41389-021-00311-4 |
| spellingShingle | Li-Peng Hu Kai-Xia Zhou Yan-Miao Huo De-Jun Liu Qing Li Min-Wei Yang Pei-Qi Huang Chun-Jie Xu Guang-Ang Tian Lin-Li Yao Xue-Li Zhang Ya-Hui Wang Jun Li Zhi-Gang Zhang Shu-Heng Jiang Xin Xing Xu Wang Wei-Ting Qin Qin Yang Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics Oncogenesis |
| title | Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics |
| title_full | Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics |
| title_fullStr | Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics |
| title_full_unstemmed | Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics |
| title_short | Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial bioenergetics |
| title_sort | single cell rna sequencing reveals that targeting hsp90 suppresses pdac progression by restraining mitochondrial bioenergetics |
| url | https://doi.org/10.1038/s41389-021-00311-4 |
| work_keys_str_mv | AT lipenghu singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT kaixiazhou singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT yanmiaohuo singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT dejunliu singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT qingli singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT minweiyang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT peiqihuang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT chunjiexu singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT guangangtian singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT linliyao singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT xuelizhang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT yahuiwang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT junli singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT zhigangzhang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT shuhengjiang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT xinxing singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT xuwang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT weitingqin singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics AT qinyang singlecellrnasequencingrevealsthattargetinghsp90suppressespdacprogressionbyrestrainingmitochondrialbioenergetics |