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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Pancreatic Cancer-Derived Small Extracellular Vesicles Remodel Hepatic Pre-Metastatic Niche via Hybrid Epithelial–Mesenchymal States

by
Francesco Balestra
1,
Giorgia Panzetta
1,
Maria De Luca
1,
Federica Rizzi
2,3,
Anna Ancona
4,
Ilaria Grassi
5,
Roberto Comparelli
2,3,
Maria Lucia Curri
2,3,6,
Gianluigi Giannelli
7,
Nicoletta Depalo
2,3,† and
Maria Principia Scavo
1,*,†
1
Laboratory of Molecular Medicine, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
2
Institute for Chemical-Physical Processes, Italian National Research Council (IPCF)-CNR SS Bari, Via Orabona, 70125 Bari, Italy
3
Bari Research Unit, National Interuniversity Consortium of Materials Science and Technology (INSTM), Via Orabona 4, 70126 Bari, Italy
4
Core Facility Biobank, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
5
Department of Pathology, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
6
Department of Chemistry, University of Bari, Via Orabona 4, 70125 Bari, Italy
7
Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, Via Turi 27, Castellana Grotte, 70013 Bari, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2026, 27(12), 5270; https://doi.org/10.3390/ijms27125270
Submission received: 20 May 2026 / Revised: 4 June 2026 / Accepted: 6 June 2026 / Published: 10 June 2026
(This article belongs to the Section Molecular Biology)
Versions Notes

Abstract

Pancreatic ductal adenocarcinoma frequently metastasises to the liver, although the mechanisms underlying hepatic pre-metastatic niche formation remain unclear. Small extracellular vesicles mediate tumour–host communication and may drive hepatic microenvironment reprogramming. This study investigated the effects of pancreatic ductal adenocarcinoma-derived small extracellular vesicles on extracellular matrix remodelling and epithelial–mesenchymal transition-related plasticity in hepatic cells. Small extracellular vesicles were isolated from pancreatic ductal adenocarcinoma cell lines (MIAPaCa-2, PANC-1) and from the serum of 25 patients, characterized, and administered to hepatic stellate (LX-2) and hepatocyte-like (HEPA-RG) cells. Cell viability and migration were evaluated by functional assays, morphology by scanning electron microscopy, and molecular changes by RT-PCR, Western blotting, and immunofluorescence. In LX-2 cells, small extracellular vesicles exposure increased metabolic activity, adhesion, and migration, while inducing morphological and molecular changes associated with extracellular matrix remodelling, including reduced collagen type I alpha 2 chain, vimentin, and E-cadherin expression. In HEPA-RG cells, viability was minimally affected, whereas migration and EMT-related plasticity were enhanced. Patient-derived small extracellular vesicles induced similar but less pronounced effects. Overall, pancreatic ductal adenocarcinoma-derived small extracellular vesicles induced early hepatic microenvironmental remodelling, supporting a potential role for tumour–liver crosstalk in pre-metastatic niche-associated processes, highlighting tumour–liver crosstalk as a potential therapeutic target.
Keywords: PDAC; small extracellular vesicles; hepatic microenvironment; liver metastasis; pre-metastatic niche PDAC; small extracellular vesicles; hepatic microenvironment; liver metastasis; pre-metastatic niche

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MDPI and ACS Style

Balestra, F.; Panzetta, G.; De Luca, M.; Rizzi, F.; Ancona, A.; Grassi, I.; Comparelli, R.; Curri, M.L.; Giannelli, G.; Depalo, N.; et al. Pancreatic Cancer-Derived Small Extracellular Vesicles Remodel Hepatic Pre-Metastatic Niche via Hybrid Epithelial–Mesenchymal States. Int. J. Mol. Sci. 2026, 27, 5270. https://doi.org/10.3390/ijms27125270

AMA Style

Balestra F, Panzetta G, De Luca M, Rizzi F, Ancona A, Grassi I, Comparelli R, Curri ML, Giannelli G, Depalo N, et al. Pancreatic Cancer-Derived Small Extracellular Vesicles Remodel Hepatic Pre-Metastatic Niche via Hybrid Epithelial–Mesenchymal States. International Journal of Molecular Sciences. 2026; 27(12):5270. https://doi.org/10.3390/ijms27125270

Chicago/Turabian Style

Balestra, Francesco, Giorgia Panzetta, Maria De Luca, Federica Rizzi, Anna Ancona, Ilaria Grassi, Roberto Comparelli, Maria Lucia Curri, Gianluigi Giannelli, Nicoletta Depalo, and et al. 2026. "Pancreatic Cancer-Derived Small Extracellular Vesicles Remodel Hepatic Pre-Metastatic Niche via Hybrid Epithelial–Mesenchymal States" International Journal of Molecular Sciences 27, no. 12: 5270. https://doi.org/10.3390/ijms27125270

APA Style

Balestra, F., Panzetta, G., De Luca, M., Rizzi, F., Ancona, A., Grassi, I., Comparelli, R., Curri, M. L., Giannelli, G., Depalo, N., & Scavo, M. P. (2026). Pancreatic Cancer-Derived Small Extracellular Vesicles Remodel Hepatic Pre-Metastatic Niche via Hybrid Epithelial–Mesenchymal States. International Journal of Molecular Sciences, 27(12), 5270. https://doi.org/10.3390/ijms27125270

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