Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic cancer

Saini Setua, Shabia Shabir, Poornima Shaji, Ana Martinez Bulnes, Anupam Dhasmana, Swathi Holla, Nivesh K. Mittal,Nirakar Sahoo, Tripti Saini, Francesco Giorgianni, Mohammad Sikander, Andrew E. Massey, Bilal Hafeez, Manish Tripathi, Vincent Diego, Meena Jaggi, Junming Yu, Nadeem Zafar, Murali Mohan Yallapu, Stephen W. Behrman

Acta Pharmaceutica Sinica B(2024)

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Abstract
The application of extracellular vehicles (EVs), particularly exosomes, is rapidly expanding in the field of medicine, thanks to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we showcase that EXs derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.
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Key words
Pancreatic cancer,Tumor adjacent normal tissue fibroblasts (NAF),Desmoplasia,Extracellular vesicles,Exosomes,Tumor targeting,Ormeloxifene,Personalized medicine
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