A research group led by Professor Cecilia Sahlgren at Åbo Akademi University and the InFLAMES Research Flagship announced on Mar. 18 the discovery of a new mechanism that directs adverse remodeling of tumor tissue during breast cancer progression. The finding could provide new treatment opportunities for aggressive forms of breast cancer that currently lack targeted therapies.
Breast cancer remains the most common cancer among women worldwide. While early-stage, localized breast cancer often has a favorable prognosis, survival rates drop significantly when the disease spreads to distant organs and forms metastases. Researchers say that beyond subtype and hormone receptor status, how cancer cells communicate with other cells in the tumor environment is increasingly recognized as a key factor influencing metastasis and drug resistance.
The study focused on Jagged1, a protein involved in cell-to-cell communication, which previous studies have shown to be highly expressed in aggressive, hormone receptor negative breast cancers. Until now, its exact role in breast cancer progression was unclear.
"In our new study, we discover that Jagged1 increases breast tumor growth and metastasis and worsens survival prognosis among patients with aggressive breast cancer," said doctoral researcher Marjaana Parikainen from the Biosciences and Drug Research program at Åbo Akademi University.
Using various model systems and patient data, researchers identified a previously unknown communication mechanism between breast cancer cells and fibroblasts mediated by Jagged1. Fibroblasts are responsible for producing and controlling the extracellular matrix—the structural network supporting tissues. "When the cancer cells expressed Jagged1 on their cell surface, it activated the nearby fibroblasts to produce more extracellular matrix, such as collagen. In addition, these Jagged1-activated fibroblasts modify the structure of the surrounding extracellular matrix, creating highly aligned matrix fibers along which the cancer cells can move as they metastasize," Parikainen said.
The team also found that high levels of Jagged1 activate another signaling system called transforming growth factor beta (TGFβ), known to promote tumor progression in late-stage breast cancer by driving fibrosis and increased tumor stiffness. "High Jagged1 promoted TGFβ activity, which in turn increased collagen deposition and matrix linearization. In addition, we showed that cancer cells start expressing even more Jagged1 in stiffer matrix environments. Previous studies have shown that TGFβ also drives Jagged1 expression. This all points to a vicious cycle that keeps promoting itself and further tumor progression," Parikainen explained.
The research was conducted in collaboration with Professor Jyrki Heino's group at the University of Turku and received funding from several Finnish foundations. The findings were published in Science Advances on March 18.
