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According to a study conducted by researchers at Weill Cornell Medicine, the spinal vertebrae, which compose the spine, originate from a unique type of stem cell that produces a protein encouraging tumor metastasis. This discovery opens up a new avenue of research into spinal disorders, sheds light on why solid tumors frequently spread to the spine, and may aid in the development of novel cancer and orthopedic therapies.
The study, published in Nature, revealed that spinal bone is generated by a distinct type of stem cell compared to other bone-producing stem cells. Using “organoids” that mimicked bones created from vertebral stem cells, scientists demonstrated that a protein called MFGE8, released by these stem cells, plays a significant role in the established tendency of tumors to migrate to the spine, more so than to long bones like those in the legs. Dr. Matthew Greenblatt, the senior author of the study, emphasized, “We suspect that many bone diseases preferentially involving the spine are attributable to the distinct properties of vertebral bone stem cells.”
In recent years, researchers like Dr. Greenblatt have discovered that different types of bone are derived from distinct types of bone stem cells. Given that vertebrae develop along a different pathway early in life compared to other bones, and also have a unique evolutionary trajectory, Dr. Greenblatt and his team hypothesized the existence of a distinct vertebral stem cell.
The researchers began by isolating skeletal stem cells, which give rise to all bone and cartilage, from various bones in lab mice based on known surface protein markers. They then examined gene activity in these cells to identify a distinct pattern associated with vertebral bone. This effort led to two significant findings. Firstly, a more precise surface-marker-based definition of skeletal stem cells as a whole was established. This new definition excluded non-stem cells that were previously included in the old stem cell definition, potentially clarifying prior research in this field. Secondly, it was confirmed that skeletal stem cells from different bones indeed exhibit systematic variations in their gene activity. From this analysis, the team identified specific markers for vertebral stem cells and confirmed their functional role in forming spinal bone through further experiments in mice and lab-dish cell cultures.
The researchers then delved into the phenomenon of the spine’s heightened susceptibility to tumor metastases, including those from breast, prostate, and lung tumors, in comparison to other bone types. While the traditional theory attributed this “spinal tropism” to blood flow patterns that preferentially direct metastases to the spine, the researchers’ experiments in animal models provided evidence that blood flow alone doesn’t explain it. Instead, they found indications pointing to vertebral stem cells as potential instigators.
Dr. Jun Sun, the study’s first author, noted, “We observed that the site of initial seeding of metastatic tumor cells was predominantly in an area of marrow where vertebral stem cells and their progeny cells would be located.”
Subsequently, the team discovered that removing vertebral stem cells eliminated the disparity in metastasis rates between spine bones and long bones. Ultimately, they determined that MFGE8, a protein secreted in higher amounts by vertebral stem cells compared to long bone stem cells, significantly contributes to spinal tropism. To validate the relevance of their findings in humans, the team collaborated with investigators at the Hospital for Special Surgery to identify the human counterparts of the mouse vertebral stem cells and characterize their properties.
The researchers are now exploring methods to inhibit MFGE8 to reduce the risk of spinal metastasis in cancer patients. Dr. Greenblatt also noted that they are studying how the distinct properties of vertebral stem cells contribute to spinal disorders, particularly within the subdiscipline of orthopedics focused on spinal conditions.
