Researchers at Okayama University have created a 3D cell-culture model of human pancreatic cancer fibrotic barrier to evaluate treatments for pancreatic ductal adenocarcinoma. They were able to significantly reduce fibrosis and improve tissue permeability to drugs by targeting the ROCK2 pathway, offering hope for overcoming treatment challenges in pancreatic cancer.
Pancreatic cancer is known to be one of the most lethal forms of cancer, making it difficult for medical experts to treat. Its aggressive nature and resistance to traditional treatments have posed a constant challenge. The tough fibrotic tissue that wraps around pancreatic tumors has been a major obstacle, making it hard for large drugs to reach the affected area. However, recent research has shown promising results in increasing drug delivery and tissue permeability, which could be a game-changer in the fight against this formidable disease.
Addressing fibrosis is crucial in improving the outcomes of pancreatic cancer treatment, which has a poor prognosis. Understanding the mechanisms behind fibrosis is essential for developing better treatment strategies for this devastating disease. Conventional models for studying fibrosis in pancreatic ductal adenocarcinoma (PDAC) often do not accurately represent the complexity of the disease. To address this, Professor Mitsunobu R. Kano and a team of researchers from Okayama University, Japan, collaborated with The University
A team of researchers from the University of Tokyo and Tohoku University has created a practical model of the fibrotic barrier found in human pancreatic cancer using cells obtained from patients. The study, which was co-authored by Prof. Hiroyoshi Y. Tanaka from Okayama University, Prof. Horacio Cabral from The University of Tokyo, and Prof. Atsushi Masamune from Tohoku University, was released online on March 29, 2024, and was officially published in the May 2024 issue of the Journal of Controlled Release.
This new model provides a convenient, fast, and highly consistent experimental platform for studying the mechanisms that drive fibrosis and evaluating potential treatments.testing the effectiveness of possible medical treatments is important. It’s crucial to understand how the extracellular matrix (ECM) remodeling contributes to fibrosis in pancreatic ductal adenocarcinoma (PDAC) in order to overcome obstacles in treatment. The researchers focused on uncovering the molecular mechanisms behind the remodeling of ECM in PDAC fibrosis to identify potential points for intervention. This could lead to enhancing tissue permeability and developing more successful treatments for pancreatic cancer.
“We used advanced techniques for cell culture, as well as molecular and pharmacological interventions, to study the signaling pathways involved in PDAC fibrosis,” said Professor Kano. “In the beginning, we evaluated the impact of 3D fibrotic tissue model. Furthermore, blocking the ROCK pathway also contributed to the enhancement of tissue permeability. We also examined the role of YAP, which is responsible for regulating cell differentiation, in mediating the effects of ROCK inhibition on ECM remodeling and tissue permeability.”
The findings provide valuable insights into potential strategies for improving drug delivery in PDAC by focusing on targeted signaling pathways related to fibrosis. The inhibition of the TGFβ pathway resulted in decreased ECM remodeling and increased tissue permeability for drug delivery.The 3D-PDAC fibrotic model showed that blocking the ROCK pathway, especially through ROCK2 inhibition, led to reduced ECM remodeling and improved drug permeability. Professor Kano stated that knockdown experiments indicated that ROCK2 plays a major role in regulating these processes. Additionally, targeting the YAP protein, which is a downstream effector of ROCK signaling, resulted in similar improvements in ECM remodeling and drug permeability. These findings demonstrate the potential of targeting the TGFβ/ROCK2/YAP signaling axis to reduce fibrotic barriers and enhance drug delivery in pancreatic cancer, offering promising prospects for improving treatment.Treatment outcomes in this difficult disease are being heavily impacted by the research. The study’s implications reach beyond just pancreatic cancer. “Fibrosis is not only common in pancreatic cancer, but also in other hard-to-treat cancers such as those affecting the stomach, breast, and lung, as well as in some non-cancerous diseases. With a lack of effective medical treatments for fibrotic conditions, our findings provide some hope for improving treatment strategies and outcomes in a wider range of fibrotic cancers and non-cancerous fibrotic conditions,” Prof. Kano concludes.
