Researchers at the Karlsruhe Institute of Technology have identified that inactivating the CD44 molecule in cancer-associated fibroblasts shrinks pancreatic tumors in mouse models by cutting off extracellular matrix production and immunosuppression. Meanwhile, a separate study demonstrates that calcitonin gene-related peptide accelerates pancreatic cancer progression by acidifying the tumor microenvironment.
Inactivating CD44 in Mouse Models
Pancreatic cancer remains exceptionally difficult to treat, largely because the dense surrounding tissue acts as a protective shield and blocks immune responses. In pancreatic tumors, this supporting tissue can account for up to 90 percent of the total mass. Researchers focused their laboratory work on cancer-associated fibroblasts, which are mutated connective tissue cells that drive tumor growth. By targeting the CD44 molecule, the team disrupted the signaling pathways that keep these fibroblast cells active.
When investigators inactivated CD44 in both human cells and mouse models, the physical characteristics of the fibroblasts shifted in a targeted manner by inactivating CD44 instead of destroying the cells entirely. This intervention altered the biological output of the supporting tissue.
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.
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), via Miragenews
Reprogrammed Connective Tissue Cells Help Immune Defenses Penetrate Tumors
The reprogramming of these connective tissue cells alters the microenvironment by removing the scar-like matrix that normally insulates cancer cells from treatment. Without the barrier, the body’s natural defenses penetrate the tumor mass more effectively. The research effort involved scientists from the Karlsruhe Institute of Technology.
Earlier investigations at the Karlsruhe Institute of Technology established that blocking certain CD44 variants on cancer cells can slow down disease progression. That earlier work led to the creation of a peptide directed at CD44v6, which has already undergone clinical testing. The latest findings indicate that extending this targeted blockade to the supporting tissue surrounding the tumor could offer a parallel therapeutic avenue, though clinical translation requires additional studies.
Neuropeptides Stimulate Pancreatic Cancer Cell Growth and Migration
In a separate investigation into the pancreatic tumor microenvironment, researchers mapped how neuronal signals influence cancer cell survival and growth. Analysis of tissue samples revealed that calcitonin gene-related peptide expression and neuronal activation markers p-ERK and p-CREB are significantly elevated in PDAC tissues. Exogenous applications of the neuropeptide stimulated PANC02 cell proliferation and migration, while knockout models suppressed orthotopic tumor growth.
Mechanistic analysis showed that the neuropeptide upregulates specific proton transporters, specifically NHE1 and CA9. This upregulation facilitates hydrogen ion efflux and lowers extracellular pH, intensifying acidity within the tumor microenvironment. Clinical data indicate that high expression levels of NHE1 and CA9 correlate with poor prognosis for patients. Treating cancer cells with exogenous calcitonin gene-related peptide decreased extracellular pH.