Pancreatic cancer is one of the most aggressive and difficult-to-treat cancers. One reason for its resistance to therapy is the dense tissue surrounding the tumor, which acts as a protective barrier and suppresses the immune response. Researchers at the Karlsruhe Institute of Technology (KIT) have now identified a molecular mechanism that regulates this tumor-supporting environment. At the heart of this mechanism is CD44, a molecule that controls the behavior of cancer-associated fibroblasts, specialized connective tissue cells that play a crucial role in shaping the tumor microenvironment.The results have been published in Cell Death & Disease (DOI: 10.1038/s41419-026-09155-5).
Tumors do not only consist of cancerous cells. They are surrounded by a complex tissue made of supporting cells, blood vessels, and immune cells – the tumor microenvironment. In pancreatic cancer, this surrounding tissue accounts for up to 90% of the tumor mass. Of particular importance are cancer-associated fibroblasts (CAFs), mutated connective tissue cells surrounding the tumor. They stimulate its growth and spread by growing a scar-like tissue structure and suppressing the body’s own immune response. As a result, many immunotherapies that help with other forms of cancer are often ineffective.
Key Role of the CD44 Molecule
In their study, the researchers focused on the role of the CD44 molecule in cancer-associated fibroblasts. They demonstrated that CD44 intensifies important signals that activates these cells. In the laboratory, they inactivated CD44 in the mouse model as well as in human cells. “This changed the fibroblasts dramatically. They produced less extracellular matrix, released fewer cytokines , and lost their ability to suppress the immune system. As a result, immune cells could attack the tumor cells more successfully, which significantly decreased the tumor size in a mouse model,” said Professor Véronique Orian-Rousseau, head of the Cancer Cell Plasticity, Tumor Microenviroment and Metastasis research group at KIT’s Institute of Biological and Chemical Systems – Functional Molecular Systems (IBCS-FMS). “The fact that we can change fibroblasts in a targeted manner by inactivating CD44 instead of destroying them opens up new prospects for more effective and less disruptive cancer treatments.”
Potential New Treatment Approaches
The study ties in with a therapy approach against CD44 already pursued at KIT. Earlier work had shown that blocking certain CD44 variants on cancer cells can slow down the progression of pancreatic cancer. Based on this finding, the researchers developed a peptide directed at CD44v6, which has already been tested in a clinical study.
The current results suggest that blocking CD44 in the supporting tissue of tumors could also be therapeutically promising. However, further research will be needed to develop a clinical application.
In addition to the KIT scientists, researchers from TRON at the University Medical Center of Johannes Gutenberg University Mainz and researchers from the University of Freiburg also took part in the study.
Original Publication
Sven Máté Treffert, Yvonne Madeleine Heneka, Julie Martin, Alessandra Gargano, Larissa Launhardt, Özlem Akilli, Eliana Stanganello, Geoffroy Andrieux, Dominique Hoch, Steffen Joachim Sonnentag, Lisa-Marie Mehner, Leonel Munoz-Sagredo, Michelle Christ & Véronique Orian-Rousseau: Loss of CD44 re-educates pancreatic cancer-associated fibroblasts modulating their fibrotic and immunosuppressive functions. Cell Death & Disease 17, 2026. DOI: 10.1038/s41419-026-09155-5. https://doi.org/10.1038/s41419-026-09155-5