Fighting pancreatic cancer remains a daunting challenge due to the disease’s complex and varied nature. Scientists have been searching for better ways to introduce therapeutic genes into cancer cells effectively. One promising method involves using viruses to carry these genes into the cells. However, finding the right virus that can consistently deliver genes to all the different subtypes of pancreatic ductal adenocarcinoma (PDAC) has been difficult. This is where the Sendai virus shows exceptional promise, offering a robust and efficient way to overcome these challenges.
Researchers from Oregon Health & Science University, led by senior author Dr. Jungsun Kim and her colleagues including first author Dr. Dmytro Grygoryev, have demonstrated that the Sendai virus (SeV) is a robust and efficient vector for delivering genes into PDAC cells. Their findings, published in the peer-reviewed journal, Heliyon, show that the Sendai virus outperforms others in terms of transduction efficiency, making it a promising tool for gene therapy in PDAC.
PDAC is notorious for its low survival rates, with the five-year survival rate being the lowest among all cancers. This is partly due to the lack of early symptoms and noninvasive markers that could facilitate early diagnosis. Understanding the molecular mechanisms of PDAC and identifying new therapeutic targets are essential for improving patient outcomes. PDAC can be grouped into “classical” and “basal, or squamous or mesenchymal” two main transcriptional subtypes, anddisplays high inter- and intra-tumoral heterogeneity. Thus, it is important to deliver transgenes to all subtypes consistently.
The team noticed that lentivirus transduces certain PDAC subtypes or normal cells in the culture derived from patients.This observation has motivated the researchers to compare the transduction efficiencies of various vectors, including vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped lentiviral vectors and adeno-associated viral (AAV) vectors, in both normal pancreatic ductal and PDAC cells derived from patients. The results consistently favored the Sendai viral vector across different PDAC subtypes, demonstrating its robust performance irrespective of the cell type. Dr. Kim stated, “The Sendai virus vector provided the most robust gene delivery efficiency, regardless of PDAC subtypes. This makes it a valuable tool for gene-based therapeutic strategies.”
The study also highlights the limitations of other viral vectors. For instance, lentiviral vectors showed variable transduction efficiencies depending on the PDAC cell type, with poor performance in classical subtype PDAC cells. Similarly, AAV vectors, though widely used, have several shortcomings, including the need for high doses and limited genomic packaging capacities. In contrast, the Sendai virus, being an RNA virus, replicates in the cytoplasm without integrating into the host genome, thereby avoiding potential genomic disruptions.
The Sendai virus offers a non-integrative approach to gene delivery, which is advantageous for maintaining the genetic integrity of the host cells. Another significant advantages of the Sendai virus is its ability to maintain transgene expression in highly dividing cells for an extended period, up to five passages. This is particularly beneficial for long-term studies and therapeutic applications where sustained gene expression is crucial. “Our findings suggest that the Sendai virus is an efficient RNA-based gene delivery vehicle, capable of long-lasting transgene expression in PDAC and normal pancreatic ductal cells,” Dr. Kim added.
The implications of this study are vast, especially for developing gene-based therapies for pancreatic cancer. The high transduction efficiency of the Sendai virus also makes it suitable for genome-wide genetic screenings, which require a low multiplicity of infections per cell. Additionally, the Sendai virus’s safety profile, having never been linked to human disease, further enhances its potential for cell therapy, such as in vivo transdifferentiation or direct reprogramming in pancreatic diseases.
Despite the promising results, the researchers acknowledge the need for further investigations to determine the extent of toxicity and efficacy in vivo, particularly in murine models where the Sendai virus cannot be used due to its pathogenicity in rodents. Future studies will also explore the applicability of the Sendai virus in three-dimensional culture settings, such as organoid cultures, to better mimic the tumor microenvironment.
In conclusion, the study by Dr. Kim and her colleagues establishes the Sendai virus as a superior gene delivery vector for PDAC derived from human patients, offering new avenues for gene-based therapeutic interventions. This work sets the stage for future research to leverage the Sendai virus’s capabilities in clinical and pre-clinical settings, potentially transforming the landscape of pancreatic cancer treatment.
Journal Reference
Grygoryev D., et al. “Sendai virus is robust 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 Kim’s long-standing interest is a reversible regulatory mechanism underlying cancer development and progression, with an ultimate goal to apply the findings in early cancer therapy. To this end, she demonstrated a proof-principle of a PDAC reprogramming model that provides a human cell model for unprecedented experimental access to different stages of human pancreatic cancer. Using this system, she uncovered a regulatory network and a secreted or released protein that can discriminate early resectable stage I pancreatic cancer patients as well as all stages of PDAC from healthy controls. Following these studies, Dr. Kim’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 networks in pluripotency transiently suppress cancer phenotypes (3) The regulatory network during the transition from precursors to invasive pancreatic cancer. She received her B.S. and Ph.D. in biochemistry from Hanyang University in South Korea under the mentorship of Dr. IL-Yup Chung, and completed postdoctoral studies at the University of Pennsylvania under the mentorship of Dr. Kenneth Zaret.
