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

Oncogene volume 44, pages 2328–2341 (2025)Cite this article

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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.

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Fig. 1: Increased secretion of TSPAN8highRAB27Bhigh exosomes in PDAC CSC.
Fig. 2: TSPAN8 is highly expressed in PDAC CSC exosomes.
Fig. 3: Exosomal TSPAN8 promotes NSCC stemness.
Fig. 4: Exosomal TSPAN8 enhance NSCC stemness via activating Hh signalling pathway.
Fig. 5: Exosomal TSPAN8 enhances malignant properties of PDAC.
Fig. 6: Exosomal TSPAN8 promotes tumourigenesis in vivo.

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Data availability

The PDAC and adjacent non-cancerous tissue scRNA-seq data were downloaded from the Gene Expression Omnibus (GEO) database with accession number GSE212966 (PRJNA879876). Corresponding analysis scripts and codes are available upon request from the lead author, Xiaoyi Yang (nicole_yang@sjtu.edu.cn).

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Acknowledgements

This work was supported by the National Key R&D Program of China (grant number 2023YFC2506400), National Natural Science Funds (grant number 82225038, 82430092, 82272828, 82172735, 32270749, 32370755, and M-0349), Shanghai Science and Technology Innovation Action Plan (grant number 23J21900900), National Science Fund for Distinguished Young Scholars Fund (grant number 82125026), Innovative research team of high-level local universities in Shanghai (grant number SHSMU-ZLCX20211600), Talent Introduction Fund of Fudan University Shanghai Cancer Center (grant number YJRC202403), Shanghai Anticancer Association SOAR PROJECT (SACA-AX202401), Natural Science Foundation of Shanghai (grant number 22ZR1450000), Shanghai leading talent project (grant number QNWS2024019). Additional support came from Medical Innovation Research Special Project of Shanghai (Grant No. 22Y11908600). All authors involved in this study have declared that they have no financial conflicts of interest in relation to this work.

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  1. These authors contributed equally: Xiaoyi Yang, Rujiao Liu, Juan Jin.

Authors and Affiliations

  1. Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xiaoyi Yang, Jingxuan Xv, Yijie Jin, Yaya Zhang, Shan Chen, Wumaier Reziya, Junjian Li & Guangjian Fan

  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

    Xiaoyi Yang & Guangjian Fan

  3. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

    Rujiao Liu, Juan Jin, Haoyu Sun, Hongxia Wang, Bo Yu & Wenting Liu

  4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Rujiao Liu, Juan Jin, Haoyu Sun, Hongxia Wang, Bo Yu & Wenting Liu

  5. Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, China

    Jiahao Wu

  6. Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China

    Bin Sun & Mou-bin Lin

  7. Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Haoyu Sun

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Contributions

XY, RZ, JX, JW, YJ, YZ, SC, BS, ML, WR, JL, RL and JJ, performed experiments. HS, HW, BY, RL, and JJ provided human samples. XY and JW performed bioinformatics analyses. XY, RZ, WL, GF, and BY interpreted data and wrote the manuscript. HW, WL, GF, and BY supervised the study and reviewed the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Bo Yu, Guangjian Fan or Wenting Liu.

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Yang, X., Liu, R., Jin, J. et al. Cancer stem cells-derived exosomal TSPAN8 enhances non-stem cancer cells stemness and promotes malignant progression in PDAC. Oncogene 44, 2328–2341 (2025). https://doi.org/10.1038/s41388-025-03412-1

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