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.

胰腺导管腺癌（PDAC）是最致命的癌症之一，缺乏有效的治疗策略。迫切需要开发新的PDAC治疗策略。PDAC癌细胞群的遗传和表型异质性在PDAC的临床管理中提出了进一步的挑战。在这项研究中，我们进行了单细胞RNA测序以表征KPC小鼠的PDAC肿瘤。功能研究和临床分析表明，具有高Hsp90表达的PDAC簇2细胞比其他簇更具侵略性。Hsp90的遗传和药理学抑制作用在体外和体内均会损害肿瘤细胞的生长。进一步的机理研究表明，HSP90的抑制作用破坏了HSP90与OPA1之间的相互作用，导致线粒体cr的减少和线粒体能量的产生。总的来说，我们的研究表明HSP90可能是PDAC的潜在治疗靶标。