Wu Yang, Zhang Chun, Huang Jiacheng, Chen Qun, Zhang Yufeng, Liu Fengyuan, Xu Dong, Jiang Kuirong, Shi Run, Chen Mengxing, Yuan Hao
Pancreas Centre, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
Semin Oncol. 2025 Apr;52(2):152338. doi: 10.1016/j.seminoncol.2025.152338. Epub 2025 Apr 17.
Pancreatic cancer is characterized by its high mortality rate and short survival periods, and novel therapeutic targets and tailor personalized strategies are urgently needed. In this study, we aim to investigate the molecular mechanisms underlying pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance, with a focus on identifying novel therapeutic targets.
Multiomics approaches were integrated to identify novel actionable targets for PDAC. Public datasets such as TCGA and GEO were utilized to investigate the relationship between gene expression and clinical outcomes. Functional enrichment, cell-cell communication, and metabolic pathway analyses were performed to reveal PDAC heterogeneity and therapeutic resistance mechanisms.
BHLHE40 was identified as a hub gene linked to high-CNV PDAC cells, Gemcitabine resistance, and poor prognosis in PDAC. High BHLHE40 expression is significantly correlated with immunosuppressive tumor microenvironment (TME) features such as reduced CD8+ T infiltration, TCR richness, and lower tumor mutational burden (TMB). ChIP-seq data analysis confirmed BHLHE40 could directly bind to the SAT1 promoter, establishing a transcriptional axis promoting chemoresistance. Single-cell RNA-seq analysis further revealed that the BHLHE40+/SAT1+ subpopulation cells are resistant to Gemcitabine in PDAC.
BHLHE40 is significantly correlated with PDAC malignancy and chemoresistance via SAT1 regulation and immune evasion. Targeting BHLHE40 may sensitize PDACs to Gemcitabine and facilitate personalized treatment for BHLHE40+ PDAC patients.
胰腺癌具有高死亡率和短生存期的特点，迫切需要新的治疗靶点和个性化治疗策略。在本研究中，我们旨在探讨胰腺导管腺癌（PDAC）进展和化疗耐药的分子机制，重点是确定新的治疗靶点。
整合多组学方法以确定PDAC的新的可操作靶点。利用TCGA和GEO等公共数据集研究基因表达与临床结果之间的关系。进行功能富集、细胞间通讯和代谢途径分析以揭示PDAC的异质性和治疗耐药机制。
BHLHE40被确定为与高拷贝数变异（CNV）的PDAC细胞、吉西他滨耐药及PDAC预后不良相关的枢纽基因。高BHLHE40表达与免疫抑制性肿瘤微环境（TME）特征显著相关，如CD8 + T细胞浸润减少、TCR丰富度降低和肿瘤突变负荷（TMB）降低。染色质免疫沉淀测序（ChIP-seq）数据分析证实BHLHE40可直接结合SAT1启动子，建立促进化疗耐药的转录轴。单细胞RNA测序分析进一步显示，BHLHE40 + /SAT1 +亚群细胞对PDAC中的吉西他滨耐药。
BHLHE40通过调控SAT1和免疫逃逸与PDAC的恶性程度和化疗耐药显著相关。靶向BHLHE40可能使PDAC对吉西他滨敏感，并有助于为BHLHE40 + PDAC患者提供个性化治疗。
