Fighting pancreatic cancer remains a daunting challenge due to the complexity and diversity of the disease. Scientists have been looking for better ways to effectively introduce therapeutic genes into cancer cells. A promising approach involves carrying these genes into cells using viruses. However, it is difficult to find a suitable virus that can consistently deliver genes to all different subtypes of pancreatic ductal adenocarcinoma (PDAC). This is where Sendai virus demonstrates its commitment to excellence, providing a solid and effective way to overcome these challenges.
Researchers at Oregon University of Health and Science, led by senior author Dr. Jungsun Kim and her colleagues, including first author Dr. Dmytro Grygoryev, have proven that Sendai virus (SEV) is a powerful and effective way to deliver genes into PDAC cells. vector. Their findings, published in the peer-reviewed journal Heliyon, show that Sendai virus is superior to others in transduction efficiency, making it a promising tool for PDAC gene therapy.
PDAC is notorious for its low survival rate, with a five-year survival rate of the lowest of any cancer. This is partly due to the lack of early symptoms and non-invasive markers that can promote early diagnosis. Understanding the molecular mechanisms of PDAC and identifying new therapeutic targets is critical to improving patient outcomes. PDAC can be divided into two main transcriptional subtypes, “classical” and “basal, squamous or interstitial”, and has high intrainflammatory and intratumoral heterogeneity. Therefore, it is important to consistently deliver the transgenic gene to all subtypes.
The team noticed that lentivirus transfers certain PDAC subtypes or normal cells in the culture derived from patients.This observation has motivated the researcher s to compare the transmission efficiency of various vectors, including vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped lentiviral vectors an d In normal pancreatic ducts and PDAC cells, the adeno-associated virus (AAV) vector is derived from the patient. The results always favor Sendai virus vectors across different PDAC subtypes, indicating their strong performance regardless of cell type. “The Sendai virus vector provides the most powerful gene delivery efficiency regardless of the PDAC subtype. This makes it a valuable tool for gene-based therapeutic strategies,” said Dr. Kim.
The study also highlights the limitations of other viral vectors. For example, lentiviral vectors show variable transduction efficiency according to PDAC cell type and have poor performance in classical subtype PDAC cells. Similarly, although widely used, AAV vectors have several disadvantages, including the need for high doses and limited genomic packaging capabilities. In contrast, Sendai virus is an RNA virus that replicates in the cytoplasm without integrating into the host genome, thus avoiding potential genome destruction.
Sendai virus provides a non-integrated gene delivery method, which is beneficial for maintaining the genetic integrity of the host cell. Another important advantage of Sendai virus is its ability to maintain transgene expression in highly divided cells over a prolonged period (up to five paragraphs). This is particularly beneficial for long-term research and therapeutic applications that are critical to sustained gene expression. Dr. Kim added: “Our findings suggest that Sendai virus is a potent RNA-based gene delivery vector capable of long-lasting transgene expression in PDAC and normal pancreatic duct cells.”
The implications of this study are broad, especially the development of gene-based pancreatic cancer therapies. The high transduction efficiency of Sendai virus also makes it suitable for genome-wide genetic screening, which requires infection diversity per cell. Furthermore, the safety of Sendai virus has never been linked to human diseases, further enhancing its potential for cellular therapy, such as in vivo transdifferentiation or direct reprogramming in pancreatic diseases.
Although the results are promising, the researchers acknowledge that further research is needed to determine the extent of toxicity and efficacy in vivo, especially in mouse models, where Sendai virus is not available in rodents. Future research will also explore the applicability of Sendai virus in three-dimensional culture environments, such as organ cultures, to better mimic the tumor microenvironment.
In summary, the research of Dr. Kim and her colleagues established Sendai virus as an excellent gene delivery vector for PDACs derived from human patients, providing new avenues for gene-based therapeutic interventions. This work lays the foundation for future research to capitalize on the ability of Sendai virus in clinical and preclinical settings, which has the potential to change the landscape of pancreatic cancer treatment.
Journal Reference
Grygoryev D. et al. “Sendai virus is powerful and consistent in delivering genes into human pancreatic cancer cells.” Heliyon, 2024. Doi: https://doi.org/10.1016/j.heliyon.2024.e27221
About the Author
Jungsun KimLong-standing interest is a reversible regulatory mechanism of cancer development and progression, with the ultimate goal of applying discoveries to early cancer treatment. To this end, she demonstrates the proven principle of the PDAC reprogramming model that provides a human cell model for different stages of human pancreatic cancer. She used the system to discover a regulatory network and a secreted or released protein that distinguishes early resectable stage I pancreatic cancer patients and all stages of PDAC from all stages of healthy controls. After these studies, Dr. King’s research will focus on the following areas. “Reprogramming and Programming of Cancer” (1) The role of reprogramming factors in cancer and the oncogene-induced barriers in reprogramming (2) The regulatory ne twins in pluripotency transiently suppress cancer phenotypes (3) The regulatory network during the transition from precursors to invasive Pancreatic cancer. She received her bachelor’s degree and a doctorate. Under the guidance of Dr. Il-Yup Chung, he has a PhD in Biochemistry from Hanyang University in South Korea and completed his postdoctoral research at the University of Pennsylvania under the guidance of Dr. Kenneth Zaret.
