Blocking the Molecule CD44 Alters Tumor-Promoting Cells in the Tumor Microenvironment and Could Make Pancreatic Cancer More Vulnerable
Image Credit: Treffert et al./KIT
(CC BY 4.0)
Scientific Frontline: Extended "At a Glance" Summary: Pancreatic Tumor Microenvironment Reprogramming
The Core Concept: Blocking the CD44 molecule in the microenvironment of pancreatic tumors alters cancer-associated fibroblasts, stripping them of their protective and immunosuppressive functions.
Key Distinction/Mechanism: Unlike traditional therapies that attempt to destroy the surrounding connective tissue, this approach biochemically reprograms it. By deactivating the CD44 molecule, fibroblasts change their structure, reduce fibrotic scar tissue formation, and halt the release of pro-inflammatory cytokines, which subsequently allows the immune system to effectively recognize and attack the cancer cells.
Major Frameworks/Components:
- Tumor microenvironment: The complex network of supportive cells, blood vessels, and immune cells that constitutes up to 90 percent of a pancreatic tumor's physical mass.
- Cancer-associated fibroblasts (CAFs): Modified connective tissue cells that promote tumor growth, build physical barriers, and suppress systemic immune responses.
- CD44 signaling: A molecular pathway that amplifies the activation of fibroblasts, driving their immunosuppressive and fibrotic behavior.
Branch of Science: Molecular Oncology, Immunology, and Cellular Biology.
Future Application: The development of highly targeted, less toxic adjuvant therapies designed to sensitize treatment-resistant solid tumors to standard immunotherapy regimens.
Why It Matters: Pancreatic cancer is exceptionally aggressive and notoriously resistant to conventional immunotherapies due to its dense, protective cellular shield. Reprogramming the tumor microenvironment, rather than destroying it, offers a promising and gentler pathway to overcome this formidable therapeutic barrier.
Pancreatic cancer is one of the most aggressive and difficult-to-treat types of cancer. One reason for this is the surrounding tissue, which protects the tumor and weakens the immune response. Researchers at the Karlsruhe Institute of Technology (KIT) have now discovered a mechanism to specifically alter this environment. The focus is on the molecule CD44, which controls certain connective tissue cells in the direct vicinity of tumors.
Tumors do not consist only of cancer cells. They are surrounded by a complex tissue of support cells, blood vessels, and immune cells, which is referred to as the tumor microenvironment. In pancreatic cancer, this surrounding tissue makes up to 90 percent of the tumor mass. Cancer-associated fibroblasts (CAFs)—altered connective tissue cells surrounding the tumor—are particularly important here. They promote its growth and spread by building a scar-like tissue structure and suppressing the body's immune response. As a result, they contribute to the fact that many immunotherapies that help with other types of cancer are often ineffective here.
Key Role of the Molecule CD44
In their study, the researchers investigated the role of the molecule CD44 in cancer-associated fibroblasts. They were able to show that CD44 amplifies an important signal that activates these cells. The researchers specifically switched off CD44 in both a mouse model and in human cells in the laboratory. "As a result, the fibroblasts changed fundamentally: they formed less connective tissue, released fewer pro-inflammatory messengers, and lost their ability to suppress the immune system. Consequently, immune cells were better able to attack the tumor cells, and tumor growth was significantly slowed in the mouse model," explains Professor Véronique Orian-Rousseau, head of the Cancer Cell Plasticity, Tumor Microenvironment and Metastasis research group at the KIT Institute of Biological and Chemical Systems—Functional Molecular Systems (IBCS-FMS). "The realization that fibroblasts can be specifically altered via CD44, rather than destroyed, opens up new perspectives for more effective and, at the same time, gentler cancer therapies."
Potential for New Therapeutic Approaches
The study builds on a therapeutic approach against CD44 already being pursued at KIT. Previous work had shown that blocking certain CD44 variants on cancer cells can slow the progression of pancreatic cancer. Based on this, the researchers developed a peptide directed against CD44v6, which has already been tested in a clinical trial.
The current results indicate that blocking CD44 in the supporting tissue of the tumor could also be therapeutically promising. However, further research is required before a clinical application can be developed.
Additional information: In addition to KIT, researchers from TRON—Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz and the University of Freiburg were involved in the study.
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Published in journal: Cell Death & Disease
Authors: 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, and Véronique Orian-Rousseau
Source/Credit: Karlsruhe Institute of Technology
Edited by: Scientific Frontline
Reference Number: ongy100626_01
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