Jagged1 protein builds a highway for breast cancer cells to spread

Abo Akademi University

Breast cancer kills not because of the primary tumor but because of what happens after - when cancer cells break free, travel through tissue, and colonize distant organs. Metastasis transforms a treatable local disease into a systemic one. For women with hormone-receptor-negative breast cancer, the most aggressive subtype, there are currently no targeted therapies to prevent that spread. A study from Finland now identifies a specific molecular mechanism that physically builds the roads cancer cells use to escape.

The protein that remodels the neighborhood

Professor Cecilia Sahlgren's research group at Abo Akademi University and the InFLAMES Research Flagship has identified how a cell-surface protein called Jagged1 drives the tissue remodeling that enables metastasis. Jagged1 was already known to appear at high levels in aggressive, hormone-receptor-negative breast cancers. What was not known was exactly what it does.

The answer, published March 18 in Science Advances, involves an intricate chain of communication between cancer cells and their neighbors. When breast cancer cells express Jagged1 on their surface, it activates nearby fibroblasts - the cells responsible for producing and maintaining the extracellular matrix, the structural scaffolding that gives tissue its form. These activated fibroblasts begin depositing more collagen than normal. But they do not just pile it up randomly. They organize it into highly aligned parallel fibers.

Those aligned fibers function like tracks. Cancer cells can move along them, gaining directional guidance as they migrate away from the primary tumor toward blood vessels and eventually to distant organs. The architecture of the tissue itself becomes an accomplice in metastasis.

A self-reinforcing cycle through TGF-beta

The mechanism does not stop with Jagged1 activating fibroblasts. The researchers discovered that high Jagged1 expression also activates the transforming growth factor beta (TGF-beta) pathway, a signaling system already known to promote tumor progression in late-stage breast cancer. TGF-beta is a master regulator of extracellular matrix remodeling - it drives fibrosis, increases tissue stiffness, and promotes the collagen deposition and alignment that the team observed.

Here is where the biology becomes particularly concerning. Stiffer tissue environments cause cancer cells to produce even more Jagged1. And TGF-beta itself also drives Jagged1 expression. The result is a positive feedback loop: Jagged1 activates TGF-beta, which remodels tissue, which makes tissue stiffer, which drives more Jagged1, which activates more TGF-beta. Each turn of the cycle accelerates tumor progression.

Doctoral researcher Marjaana Parikainen, who led much of the experimental work, described it as a vicious cycle that keeps promoting itself. Breaking that cycle at any point could, in theory, slow or halt the cascade that leads to metastasis.

From cell models to patient data

The team validated their findings across multiple experimental systems, including various cancer model systems, and cross-referenced their molecular observations with data from breast cancer patients. The patient data confirmed that high Jagged1 expression correlates with increased tumor growth, greater metastasis, and worse survival prognosis specifically in aggressive breast cancer subtypes.

The collaboration with Professor Jyrki Heino's group at the University of Turku provided expertise in collagen biology and extracellular matrix analysis, strengthening the mechanistic claims. The consistency across lab models and clinical data gives the findings more weight than either would carry alone.

Limitations and the road to treatment

Several important limitations apply. The cancer model systems used in the study, while informative, do not fully replicate the complexity of human tumors growing in a living body. The tumor microenvironment involves immune cells, blood vessels, and mechanical forces that cannot be captured completely in laboratory models. Whether disrupting Jagged1 signaling in patients would actually slow metastasis without causing unacceptable side effects is entirely unknown at this stage.

Jagged1 is part of the Notch signaling pathway, which plays essential roles in normal tissue development and maintenance. Blocking it broadly could cause toxicity in healthy tissues. Any therapeutic approach would need to be carefully targeted to avoid disrupting Jagged1's normal functions.

The patient data is correlational. It shows that high Jagged1 expression is associated with worse outcomes, but it does not prove that Jagged1 causes those outcomes in the clinical setting. Other molecular changes that accompany aggressive cancer subtypes could be confounding factors.

Why this matters for hormone-receptor-negative breast cancer

Breast cancer is the most common cancer among women worldwide. For patients with hormone-receptor-positive tumors, targeted therapies like tamoxifen and aromatase inhibitors have transformed prognosis. But hormone-receptor-negative cancers lack those therapeutic handles. Chemotherapy remains the mainstay, and outcomes are significantly worse.

Identifying specific molecular mechanisms like the Jagged1-TGF-beta-collagen axis gives drug developers something to aim at. If the positive feedback loop can be interrupted - whether by blocking Jagged1, inhibiting TGF-beta in the tumor microenvironment, or preventing collagen alignment - it could open a new category of treatment for patients who currently have few options.

That possibility is genuinely important. But it remains exactly that - a possibility supported by strong preclinical evidence that has not yet been tested in patients. The distance between identifying a mechanism and delivering an effective drug remains vast, and it would be irresponsible to frame this as anything closer than an early-stage discovery with therapeutic potential.