A research team in Japan has found a way to weaken the dense scar-like tissue that blocks drugs from reaching pancreatic tumors. By targeting collagen signaling, they boosted the movement of antibody and nanomedicine therapies through a 3D cancer model.
Pancreatic cancer is notorious for being one of the hardest cancers to treat. Now, scientists in Japan say they have found a way to weaken one of its biggest defenses: a dense, scar-like wall of tissue that keeps powerful drugs from reaching tumor cells.
In a new study published in the journal Small, researchers from Okayama University and Tohoku University report that blocking a key collagen signaling pathway can open up this fibrotic barrier and improve the delivery of large, modern cancer drugs in a laboratory model of pancreatic cancer.
The work centers on collagen, a structural protein that helps give tissues their shape and strength. In pancreatic tumors, collagen piles up in thick layers, creating a stiff, fibrotic microenvironment that acts like armor around cancer cells. That armor has long been blamed for the poor performance of many therapies, including antibody drugs and nanomedicines, which are larger than traditional chemotherapy molecules.
The study, led by Hiroyoshi Y. Tanaka, an assistant professor in the Graduate School of Medicine, Dentistry and Pharmaceutical Sciences at Okayama University, goes a step further. It shows that collagen is not just a physical barrier, but also a biochemical messenger that actively worsens fibrosis and blocks drug penetration.
Tanaka and his colleagues focused on discoidin domain receptor 1, or DDR1, a receptor on cell surfaces that is activated by collagen. When collagen binds to DDR1, it triggers signaling pathways that promote more fibrosis, tightening the tumor’s outer shell.
“Our findings reveal that collagen signaling, not just its physical density, plays a crucial role in hindering drug delivery,” Tanaka said in a news release.
The team built an advanced three-dimensional cell culture model that mimics the fibrotic environment of human pancreatic cancer. Unlike flat cell cultures in a dish, 3D models better capture how cells and extracellular matrix, including collagen, interact in real tumors.
Using this model, the researchers tested what happens when DDR1 signaling is blocked. They found that inhibiting DDR1 suppressed collagen-driven signaling and allowed macromolecular drugs, such as antibody therapies and nanomedicines, to diffuse more easily through the fibrotic tissue.
“By inhibiting DDR1, we can interrupt this signaling cascade, loosen the fibrotic barrier, and enable better access for therapeutic agents,” Tanaka added.
Along the way, the researchers uncovered a surprising and potentially important complication involving a class of drugs called MEK inhibitors. These drugs, which target a growth-promoting pathway in cancer cells, have been tested in pancreatic cancer but have not delivered the hoped-for benefits in clinical trials.
In the 3D model, MEK inhibitors did attack cancer cells, but they also increased the production of collagen I, a major component of the fibrotic barrier. That extra collagen thickened the tissue around the tumor and made it even harder for drugs to get through.
“We found that while MEK inhibitors can attack cancer cells, they also unintentionally strengthen the fibrotic barrier, making drug penetration even more difficult,” added Tanaka.
The team described this as therapy-induced exacerbation of the fibrotic barrier. In other words, a drug meant to fight cancer might be helping the tumor defend itself by reinforcing the collagen shield.
Crucially, when DDR1 signaling was blocked, this harmful side effect was reversed. The fibrotic barrier relaxed, and drug movement improved again. That suggests that combining DDR1 inhibitors with drugs like MEK inhibitors could make those treatments more effective by preventing the tumor from hardening its defenses.
“Recognizing and countering this effect could fundamentally change how combination therapies are designed for pancreatic cancer,” Tanaka added.
Pancreatic cancer has some of the lowest survival rates among major cancers, in part because it is often diagnosed late and resists many treatments. Its fibrotic microenvironment is a major reason why. The new findings highlight that tackling this environment is not just about breaking down physical barriers, but also about disrupting the signaling networks that sustain them.
Beyond pancreatic cancer, the work could have implications for other fibrotic diseases, where collagen buildup limits how well drugs can reach their targets. Conditions such as liver fibrosis, lung fibrosis and certain heart diseases also involve excessive collagen and stiffened tissues.
By redefining collagen as both a structural and signaling component, the study points toward a broader strategy: pair drugs that attack cancer cells or diseased tissue with agents that reprogram or relax the surrounding fibrotic matrix.
The researchers say the next step is to validate DDR1 inhibition in more advanced models and, eventually, in clinical settings. They aim to design combination treatments that simultaneously target tumor cells and their fibrotic surroundings, with the goal of helping life-saving drugs reach where they are needed most.
As pancreatic cancer continues to challenge oncologists worldwide, this collaborative effort from Okayama and Tohoku universities offers a hopeful direction: instead of just making stronger drugs, change the battlefield so that existing and future therapies can finally get through.
Source: Okayama University