Notch2 and CXCR4 Identified as Key Drivers of Breast Cancer Dormancy in Bone Marrow
核心洞察
Researchers led by Professor Anna Teti at the University of L'Aquila discovered that Notch2 (搜索), not Notch1, is the dominant signaling protein driving breast cancer (搜索) cell dormancy in bone marrow endosteal niches.
Dormant cancer cells mimic hematopoietic stem cells by expressing CXCR4 (搜索), CD34 (搜索), and TIE2 (搜索), and activate stress-response pathways including the unfolded protein response to survive long-term.
High CD177 (搜索) expression was identified as a new marker linked to dormant breast cancer (搜索) cells, associated with reduced proliferation and improved patient survival outcomes.
A research team led by Professor Anna Teti from the Department of Biotechnological and Applied Clinical Sciences at the University of L'Aquila, Italy, has uncovered new molecular pathways that regulate breast cancer (搜索) cell dormancy in bone marrow. The study, conducted in collaboration with Ludwig Maximilian University of Munich and the University of Southern Denmark, was published online in Volume 14 of Bone Research on May 14, 2026.
The findings address a long-standing challenge in breast cancer (搜索) treatment: the ability of cancer cells to remain hidden in the bone marrow for years, sometimes decades, before reactivating and causing secondary tumors in bone and other organs. This phenomenon occurs when a small number of cancer cells migrate to the bone marrow and enter a dormant or inactive state, eventually "waking up" to aggressively form metastases.
How Cancer Cells Exploit the Bone Marrow Niche
Bone marrow contains specialized microenvironments known as niches, which regulate the behavior of stem cells. The endosteal niche, located near the bone surface, contains bone-forming cells called osteoblasts. Previous studies have suggested that these niches may shelter dormant cancer cells, but the underlying mechanisms remained poorly understood.
"We discovered that breast cancer (搜索) cells can exploit the same protective systems that normally maintain healthy stem cells in bone marrow," explained Professor Teti. "This allows cancer cells to remain hidden and potentially reactivate years later."
Notch2 (搜索) Emerges as the Dominant Dormancy Regulator
The research team focused on two closely related signaling proteins, Notch1 and Notch2 (搜索), which help cells communicate with their environment and control critical cellular functions. Through a combination of imaging methods, gene expression analysis, and laboratory experiments, the researchers found that Notch2 plays the dominant role in dormancy, while Notch1 does not exhibit similar effects.
Breast cancer (搜索) cells with high levels of Notch2 (搜索) divided much more slowly while interacting with specialized osteoblasts in the endosteal niche. Slow cell division is a hallmark of cellular dormancy. In contrast, cells with high Notch1 levels did not display comparable dormant behavior.
Stem Cell-Like Properties and Gene Expression Patterns
RNA sequencing revealed that Notch2 (搜索)-rich cells showed reduced activity of genes involved in cell growth and division, while simultaneously activating genes associated with hematopoietic stem cells—the cells that produce blood cells in bone marrow. Specifically, dormant cancer cells expressed high levels of CXCR4 (搜索), CD34 (搜索), and TIE2 (搜索), genes that help stem cells survive within the bone marrow niche.
Further experiments demonstrated that cells with elevated CXCR4 (搜索) or TIE2 (搜索) levels formed fewer and smaller bone tumors in mice, suggesting reduced cancer spread.
"This was a particularly interesting finding because it suggests that cancer cells can acquire stem cell-like properties to evade treatment and survive in the body for very long periods," remarked Professor Teti.
Stress-Response Pathways and the CD177 (搜索) Marker
The study also revealed that cells with high Notch2 (搜索) expression activated stress-response pathways known as the unfolded protein response, which helps cells survive under stressful conditions. These cells showed elevated levels of molecules including PERK, ATF4, CHOP, and CD177 (搜索)—a newly identified marker linked to dormant breast cancer (搜索) cells.
Notably, CD177 (搜索)-high cells also demonstrated high Notch2 (搜索) and CXCR4 (搜索) expression, reduced cell proliferation, and were associated with improved patient survival outcomes.
Therapeutic Implications
The identification of Notch2 (搜索), CXCR4 (搜索), CD177 (搜索), and stress-response pathways as key regulators of dormancy opens new possibilities for therapies aimed at eliminating dormant cancer cells or preventing their reactivation. Such approaches could significantly reduce the risk of cancer relapse in breast cancer (搜索) patients, addressing one of the most persistent challenges in oncology.