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Published on: March 22, 2019
Single-cell RNA sequencing reveals that targeting HSP90 suppresses PDAC progression by restraining mitochondrial
Li-Peng Hu1, Kai-Xia Zhou1, Yan-Miao Huo2
1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
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.
Insights
Heat shock protein 90 (Hsp90) inhibition effectively targets aggressive pancreatic ductal adenocarcinoma (PDAC) cells. This study reveals Hsp90 as a promising therapeutic target for treating this deadly cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited therapeutic options.
- Tumor cell heterogeneity complicates effective clinical management of PDAC.
- Novel therapeutic strategies are urgently needed for PDAC treatment.
Purpose of the Study:
- To investigate the therapeutic potential of targeting Heat shock protein 90 (Hsp90) in pancreatic ductal adenocarcinoma.
- To characterize the role of Hsp90 in PDAC aggressiveness and mitochondrial function.
Main Methods:
- Single-cell RNA sequencing of KPC mouse PDAC tumors.
- In vitro and in vivo functional studies.
- Mechanistic investigations into Hsp90-OPA1 interaction and mitochondrial energy production.
Main Results:
- PDAC cluster 2 cells exhibited high Hsp90 expression and aggressive behavior.
- Genetic and pharmacologic inhibition of Hsp90 significantly reduced tumor cell growth.
- Hsp90 inhibition disrupted Hsp90-OPA1 interaction, impairing mitochondrial function and energy production.
Conclusions:
- Hsp90 plays a critical role in PDAC cell aggressiveness and mitochondrial homeostasis.
- Targeting Hsp90 presents a viable therapeutic strategy for pancreatic ductal adenocarcinoma.
- Hsp90 inhibition offers a promising avenue for novel PDAC treatment development.
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