Myoferlin: a promising target to reduce tumor fibrosis
Pancreatic cancer is notorious for its resistance to therapy. One major reason? Its particularly dense tumor microenvironment, also called stroma, made up of fibrotic tissue that protects the tumor and promotes its progression. This “shield” is largely formed by cancer-associated fibroblasts (CAFs)—cells that actively support tumor growth and produce a fibrous protein matrix.
A new approach to weaken the “shield” of pancreatic cancer
A team from Olivier Peulen’s laboratory investigated the role of a protein called myoferlin within this unique environment.
“Pancreatic ductal adenocarcinoma is characterized by a dense tumor microenvironment, mainly produced by cancer-associated fibroblasts,” the authors note.
Myoferlin: a key player in tumor–stroma communication
By analyzing human tumor samples and experimental models, the researchers found that myoferlin is highly expressed in the stroma, the tissue surrounding cancer cells. Their findings are clear:
“Stromal abundance of myoferlin correlates with increased tumor desmoplasia and decreased patient survival.”
In other words, the more myoferlin is present, the greater is the fibrous shield and the poorer is the patient prognosis.
Using single-cell RNA sequencing, the team demonstrated that myoferlin is expressed across different CAF subtypes, with a particularly crucial role in myofibroblastic CAFs (myCAFs). When the protein is deleted from these cells, “extracellular matrix production, migration, and contractility” of CAFs are reduced, meaning the production of the fibrous shield is less efficient and CAFs become far less aggressive
A protein at the heart of intracellular trafficking
On a mechanistic level, the researchers identified a key process: myoferlin facilitates the transport of the TGFβ receptor (TGFBR1) within the cell. This receptor plays a major role in the signaling pathway that drives tumor fibrosis.
“Myoferlin facilitates COPII-dependent transport of the TGFβ receptor from the endoplasmic reticulum to the Golgi apparatus,” explains Olivier Peulen.
When myoferlin is absent, this transport is disrupted: TGFβ signaling collapses, and the genes responsible for producing the extracellular matrix are no longer activated.
Toward a new therapeutic strategy
The researchers then tested what happens when myoferlin is blocked, either genetically or pharmacologically. In both cases, tumor fibrosis was significantly reduced.
“Genetic deletion of myoferlin in stromal cells and its pharmacological inhibition reduce tumor fibrosis without affecting tumor mass,” notes Raphaël Peiffer, first author of the study.
This finding is crucial: it shows that it is possible to weaken the fibrotic shield surrounding the tumor without promoting its growth.
A new avenue to improve treatment outcomes
In conclusion, the study highlights myoferlin as a key regulator of vesicular trafficking in CAFs, paving the way for an innovative approach, reprogramming the tumor stroma rather than destroying it.
“Targeting myoferlin could represent an innovative strategy to modulate the tumor microenvironment and reduce desmoplasia in pancreatic cancer,” concludes Olivier Peulen.
By acting on the tissue surrounding the tumor, this strategy could make pancreatic cancer more vulnerable to existing therapies or even allow the use of treatments previously reserved for less fibrous tumors, a promising step forward in the fight against one of the deadliest forms of cancer.
Reference
EMBO J. 2025 Oct 8. doi: 10.1038/s44318-025-00570-6. Online ahead of print.
