Cancer stem cells-derived exosomal TSPAN8 enhances non-stem cancer cells stemness and promotes malignant progression in PDAC

Xiaoyi Yang; Rujiao Liu; Juan Jin; Jingxuan Xv; Jiahao Wu; Yijie Jin; Yaya Zhang; Shan Chen; Bin Sun; Mou-Bin Lin; Wumaier Reziya; Junjian Li; Haoyu Sun; Hongxia Wang; Bo Yu; Guangjian Fan; Wenting Liu

doi:10.1038/s41388-025-03412-1

Cancer stem cells-derived exosomal TSPAN8 enhances non-stem cancer cells stemness and promotes malignant progression in PDAC

Oncogene. 2025 Apr 18. doi: 10.1038/s41388-025-03412-1. Online ahead of print.

Authors

Xiaoyi Yang^#^{1

2}, Rujiao Liu^#^{3

4}, Juan Jin^#^{3

4}, Jingxuan Xv¹, Jiahao Wu⁵, Yijie Jin¹, Yaya Zhang¹, Shan Chen¹, Bin Sun⁶, Mou-Bin Lin⁶, Wumaier Reziya¹, Junjian Li¹, Haoyu Sun^{3

4

7}, Hongxia Wang^{3

4}, Bo Yu^{8

9}, Guangjian Fan^{10

11}, Wenting Liu^{12

13}

Affiliations

¹ Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁵ Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁶ Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
⁷ Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁸ Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. yudky@163.com.
⁹ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. yudky@163.com.
¹⁰ Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. gjfan@shsmu.edu.cn.
¹¹ Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine; State Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. gjfan@shsmu.edu.cn.
¹² Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. liuwenting1015@163.com.
¹³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. liuwenting1015@163.com.

^# Contributed equally.

PMID: 40251391
DOI: 10.1038/s41388-025-03412-1

Abstract

Cancer stem cells (CSC) play a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance. However, the underlying mechanisms and potential targeted treatment strategies remain poorly understood. In this study, we employed single-cell RNA sequencing and exosomal profiling, identifying TSPAN8-enriched exosomes secreted by CSC, which are associated with poor survival rates in PDAC patients. They enhanced stemness in the surrounding non-stem cancer cells (NSCC) by activating the Sonic Hedgehog (Hh) signalling pathway. This exosomal TSPAN8-Hh signalling axis significantly increases the clonogenic ability, invasiveness, and chemoresistance of PDAC cells. Furthermore, TSPAN8-enriched exosomes promoted a higher stem cell frequency, tumourigenicity, and tumour growth rate in vivo, confirming their critical roles in PDAC malignant progression. Our findings underscore the importance of TSPAN8-enriched exosomes for CSC-NSCC communication during PDAC progression.