Pancreatic cancer is one of the deadliest malignancies, with survival rates remaining dismally low despite major advances in oncology. One of the key reasons lies in the disease's unique fibrotic microenvironment—a dense, collagen-rich tissue that acts as a physical and biochemical barrier, preventing drugs from reaching tumor cells effectively.
Now, a research team from Okayama University and Tohoku University has uncovered a promising new way to breach this barrier. Led by Assistant Professor Hiroyoshi Y. Tanaka from the Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, the group demonstrated that blocking collagen signaling through the discoidin domain receptor 1 (DDR1) significantly improves the delivery of macromolecular drugs in pancreatic cancer. Their study, published online on October 31, 2025, in the journal Small , highlights a new therapeutic approach to enhance drug effectiveness by dismantling fibrotic resistance mechanisms.
The research was spearheaded by Ms. Mayu Ohira and Ms. Moe Kitamura, co-first authors from Okayama University, and carried out in close collaboration with Professor Atsushi Masamune of Tohoku University and Professor Mitsunobu R. Kano of Okayama University. Together, the team investigated how collagen—long considered merely a structural barrier—also acts as a signaling molecule that directly influences fibrosis and drug penetration.
"Our findings reveal that collagen signaling, not just its physical density, plays a crucial role in hindering drug delivery," explained Dr. Tanaka, a co-author from Okayama University, Japan. "By inhibiting DDR1, we can interrupt this signaling cascade, loosen the fibrotic barrier, and enable better access for therapeutic agents."
The team leveraged an advanced three-dimensional cell culture model that replicates the human pancreatic cancer fibrotic barrier. Through this model, they demonstrated that DDR1 inhibition suppresses collagen signaling and enhances the diffusion of macromolecular drugs, such as antibodies and nanomedicines.
The study also uncovered an unexpected twist: MEK inhibitors, a class of drugs previously tested in pancreatic cancer, were found to increase collagen I expression, intensifying the fibrotic barrier and reducing treatment efficacy. Remarkably, this fibrosis-promoting effect was reversed when DDR1 signaling was blocked.
This newly identified phenomenon, termed 'therapy-induced exacerbation of the fibrotic barrier,' may explain why some MEK inhibitor-based therapies have failed in clinical trials. "We found that while MEK inhibitors can attack cancer cells, they also unintentionally strengthen the fibrotic barrier, making drug penetration even more difficult," said Dr. Tanaka. "Recognizing and countering this effect could fundamentally change how combination therapies are designed for pancreatic cancer."
The researchers emphasized the broader significance of their discovery, noting that a better mechanistic understanding of collagen signaling in fibrosis could lead to new therapeutic strategies across oncology. The team hopes that future studies will validate DDR1 inhibition in clinical settings and pave the way for translational applications in human patients. Looking forward, the team plans to establish combination treatments that simultaneously target tumor cells and their fibrotic surroundings.
Beyond pancreatic cancer, the implications of this study extend to other fibrotic diseases where collagen accumulation limits drug access. By redefining collagen's role as both a structural and signaling component, the researchers believe their work could inform the development of more effective treatments for fibrotic conditions.
As pancreatic cancer continues to pose one of the most formidable challenges in modern oncology, this collaborative study offers new hope, illuminating how rethinking fibrosis might finally help life-saving drugs reach their targets.
About Okayama University, Japan
As one of the leading universities in Japan, Okayama University aims to create and establish a new paradigm for the sustainable development of the world. Okayama University offers a wide range of academic fields, which become the basis of the integrated graduate schools. This not only allows us to conduct the most advanced and up-to-date research, but also provides an enriching educational experience.
Website: https://www.okayama-u.ac.jp/index_e.html
About Dr. Hiroyoshi Y. Tanaka from Okayama University, Japan
Dr. Hiroyoshi Y. Tanaka is an Assistant Professor at the Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan. His research spans nanomedicine, biomaterials, vascular and tumor biology, and fibrosis. A recipient of the 2025 Young Investigator Award from the Japanese Cancer Association, he focuses on nanobiotechnology-driven drug delivery and therapeutic innovations for cancer and fibrotic diseases.
