STN1 facilitates metastasis by promoting transcription of EMT-activator ZEB1 in pancreatic cancer

• Published in: Nature communications Vol. 16; no. 1; pp. 7815 - 16
• Main Authors: Dong, Di, Zhou, Zhe, Zhu, Minglu, Hou, Zhiyuan, Chen, Mo, Gong, Jingjing, Zhao, Xuyang, Yan, Aohui, Liang, Hui, Yin, Yuxin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.08.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/109; 13/44; 13/51; 38/1; 38/15; 38/32; 38/39; 38/43; 38/77; 38/91; 631/67/322; 631/67/395; 631/80/304; 692/4020/1503/1712/1713; Adenocarcinoma; Cancer; Datasets; Genomes; Humanities and Social Sciences; Maintenance; Medical prognosis; Metastases; Metastasis; multidisciplinary; Pancreatic cancer; Pathogenesis; Patients; Proteins; Science; Science (multidisciplinary); Single-stranded DNA; Stat3 protein; Statistical significance; Telomeres; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-63083-0

Pancreatic ductal adenocarcinoma (PDAC) poses a serious clinical challenge, demanding further exploration of its pathogenesis and therapeutic targets for metastasis, the main cause of mortality. Here, we identify STN1, a CST complex member crucial for maintaining telomere lengths and genome stability, as a key factor in promoting PDAC metastasis. Elevated STN1 levels correlate with poor patient survival, with oncogenic protein HOXB7 as an upstream transcription factor regulating STN1 . Utilizing multiple PDAC experimental models, we discover STN1’s role in promoting metastasis by functioning as an upstream factor in epithelial-mesenchymal transition (EMT). Our mechanistic evidence suggests that during transcription, STN1 binds to structurally displaced single-stranded DNA flanking the R-loop, recruiting STAT3 to activate ZEB1 transcription independent of its known telomere maintenance function. Notably, STAT3 inhibitors show enhanced efficiency in restraining metastatic potential in STN1-overexpressed PDAC cells, offering a potential therapeutic avenue for targeting metastasis in STN1-overexpressed PDAC patients facing an unfavorable prognosis. Metastasis of pancreatic cancer has been associated with epithelial-mesenchymal transition (EMT). Here, the authors identify STN1 as a regulator of pancreatic cancer metastasis by promoting transcription of EMT-activator ZEB1, which is independent of its known role in telomere maintenance.