Depleting a single clotting protein shrinks pancreatic tumors and blocks liver spread in mice

Depleting fibrinogen, a clotting protein made by the liver, shrinks primary pancreatic tumors and dramatically reduces their ability to spread to the liver in mouse models. That is the core finding from a study led by Melissa L. Fishel at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center, published in Gastroenterology.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers. When it metastasizes to the liver, prognosis collapses. Patients with pancreatic cancer also have some of the highest rates of blood clots and deep-vein thrombosis of any cancer type. Fishel's team wanted to determine whether the proteins involved in blood coagulation are actively driving the disease or are merely a byproduct of it.

Fibrin everywhere the tumor grows

Fibrinogen is a large protein produced by the liver that gets cleaved into fibrin after an injury, forming the structural scaffold of blood clots. In healthy pancreas tissue, the team found very little fibrin. On pancreatic tumor samples, fibrin was abundantly deposited.

Pancreatic tumors are notorious for their dense, fibrotic microenvironment, a stiff matrix of proteins and cancer-associated fibroblasts that surrounds and supports the tumor. Fibrin, it turns out, is a major component of this supportive scaffold. The question was whether removing it would change anything.

Two methods, same result

Using two different methods to deplete fibrinogen in mouse models, the researchers saw dramatic effects. Primary tumors grew smaller. Liver metastases, the event that most sharply worsens patient outcomes, were far fewer.

But the mechanism was not what you might initially guess. The team also tested whether fibrin circulating in the bloodstream was helping cancer cells establish new colonies after they had already left the pancreas. They used tumor models that produced metastases in the liver or lung, then depleted fibrinogen. There was no difference in metastatic growth at the distant sites.

This means the effect is local, not systemic. Something about the absence of fibrin at the primary tumor site changes the tumor cells themselves. They become either less likely to leave the pancreas or somehow unable to establish liver lesions once they do.

Returning to baseline, not to zero

The body needs fibrinogen to prevent excessive bleeding, so eliminating it entirely in patients is not an option. Fishel noted that fibrinogen levels are elevated in pancreatic cancer patients, and the therapeutic concept would be to return those levels to baseline rather than to deplete them completely. The team believes this could be clinically manageable.

The next steps involve combining fibrinogen-targeted approaches with chemotherapy or emerging pancreatic cancer therapies. In the mouse models, reducing fibrinogen delayed disease progression but did not constitute a cure. Understanding what fibrin turns on or off in the tumor could reveal combination strategies that make existing treatments more effective.

From clotting research to cancer target

The study used multiple tumor cell models, including two derived from IU patient samples developed by the cancer center's Pancreatic Cancer Working Group. It was conducted as part of the Pancreatic Cancer Stromal Reprogramming Consortium, a multi-site national collaboration.

The connection between clotting and cancer is not new. Clinicians have long observed that cancer patients are at elevated risk for thrombotic events. But most efforts have focused on anticoagulation to prevent clots, not on targeting the clotting proteins as a way to fight the tumor itself. The IU study opens a different angle: treating the tumor's structural support system.

Important caveats

This is preclinical work in mouse models. The leap from shrinking tumors in mice to effective therapy in human patients is long, uncertain, and littered with candidates that did not survive the transition. Mouse models of pancreatic cancer, while improved in recent years, do not perfectly replicate the complexity of human disease.

The study also does not explain the molecular mechanism by which the absence of fibrin changes tumor cell behavior. That is the focus of ongoing work. Without understanding the downstream signaling, it will be difficult to design drugs that specifically target the relevant pathway rather than broadly depleting a protein the body needs.

Still, for a cancer with a five-year survival rate that remains in the single digits, any new angle of attack is worth pursuing.