Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors

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 B Hafeez; Manish K Tripathi; Vincent P Diego; Meena Jaggi; Junming Yue; Nadeem Zafar; Murali M Yallapu; Stephen W Behrman; Sheema Khan; Subhash C Chauhan

doi:10.1016/j.apsb.2024.04.003

Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors

Acta Pharm Sin B. 2024 Jul;14(7):3009-3026. doi: 10.1016/j.apsb.2024.04.003. Epub 2024 Apr 9.

Authors

Saini Setua¹, Shabia Shabir², Poornima Shaji^{3

4}, Ana Martinez Bulnes^{3

4}, Anupam Dhasmana^{3

4

5}, Swathi Holla³, Nivesh K Mittal⁶, Nirakar Sahoo⁷, Tripti Saini⁷, Francesco Giorgianni¹, Mohammad Sikander^{1

3

4}, Andrew E Massey^{1

8}, Bilal B Hafeez^{1

3

4}, Manish K Tripathi^{1

3

4}, Vincent P Diego⁹, Meena Jaggi^{1

3

4}, Junming Yue¹, Nadeem Zafar¹⁰, Murali M Yallapu^{1

3

4}, Stephen W Behrman^{1

11

12}, Sheema Khan^{1

3

4}, Subhash C Chauhan^{1

3

4}

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, and College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 36163, USA.
² Department of Computer Science, Islamic University of Science and Technology, Awantipora, J&K 192122, India.
³ Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA.
⁴ South Texas Center of Excellence in Cancer Research, School of Medicine, the University of Texas Rio Grande Valley, McAllen, TX 78504, USA.
⁵ Himalayan School of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun 248016, India.
⁶ Plough Center for Sterile Drug Delivery Solutions, UTHSC, Memphis, TN 38104, USA.
⁷ Department of Biology, College of Sciences, UTRGV, McAllen, TX 78539, USA.
⁸ National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health, Bethesda, MD 20892, USA.
⁹ South Texas Diabetes and Obesity Institute, UTRGV, McAllen, TX 78504, USA.
¹⁰ Dept. of Laboratory Medicine & Pathology, University of Washington, Seattle, WA 98195, USA.
¹¹ Department of Surgery, Baptist Memorial Medical Education, Baptist Memorial Hospital, Memphis, TN 38120, USA.
¹² Baptist Health Sciences University, Memphis, TN 38104, USA.

Abstract

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing 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 show that exosomes (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 of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Keywords: Desmoplasia; Exosomes; Extracellular vesicles; Ormeloxifene; Pancreatic cancer; Personalized medicine; Tumor adjacent normal tissue fibroblasts (NAF); Tumor targeting.