BIDMC Researchers Identify Gene Driving Colorectal Cancer Development
Loss of COSMC Gene Destroys Gut’s Protective Barrier
BOSTON — Scientists at Beth Israel Deaconess Medical Center (BIDMC) have answered a question that has puzzled cancer researchers for decades: Does a genetic defect found in nearly all human colorectal cancers simply accompany the disease, or does it actually trigger its development?
In laboratory experiments, deleting a single gene called COSMC (C1GalT1C1) found in the lining of the intestines led to the development of invasive colorectal cancer within a year in a rodent model. The findings, published in the Journal of Biological Chemistry, settle a longstanding debate about whether this genetic defect is a cause or consequence of cancer.
“We've demonstrated that losing this single gene is enough to trigger the entire disease process,” said senior author Richard D. Cummings, PhD, the S. Daniel Abraham Professor of Surgery and division chief of Surgical Sciences at BIDMC, as well as director of the Harvard Medical School Center for Glycoscience. “We've shown that the same molecular change found in the vast majority of human colorectal cancers is sufficient on its own to cause tumors to develop.”
That molecular change is the Tn antigen, a marker that appears on cell surfaces as a result of the COSMC gene failing.
Colorectal cancer is projected to cause 52,900 deaths in the United States in 2025, making it the second-leading cause of cancer death after lung cancer. Most cases occur in the rectum and lower colon.
The COSMC gene is essential for building the protective mucus layer that shields intestinal cells from trillions of gut bacteria. Without that gene functioning properly, that protective barrier — normally thinner than the wall of a soap bubble — vanishes. Without it, intestinal cells lose an important line of defense and become vulnerable to the damage that leads to cancer.
In the current study, invasive tumors were seen in the rectum and lower colon — the same region where most human colorectal cancers occur. Laboratory analysis confirmed that all tumors expressed the Tn antigen, verifying they arose from COSMC-deficient cells.
Because the Tn antigen appears on the surface of cancer cells but not on healthy cells, it represents a promising target for precision therapy. The research team is now developing a monoclonal antibody that targets the Tn antigen on tumor cells as a potential treatment for colorectal cancer and other malignancies where Tn is expressed.
The study was led by laboratories at BIDMC and the U.S. Food and Drug Administration, with additional contributions from investigators who conducted the work at Emory University School of Medicine before the BIDMC team's recent relocation to Boston.
Co-authors included Matthew R. Kudelka and Xiaodong Sun of Beth Israel Deaconess Medical Center (BIDMC); and Tongzhong Ju, Yingchun Wang, Hikaru Nishio, Jianmei Wang, Junwei Zeng, Lina Song, Gizem Akkas, Volkan Adsay, and Charles A. Parkos of Emory University School of Medicine.
This work was supported by grants from the National Institutes of Health (U01CA168930 and R01DK80876 to T.J.; R01DK072564, R01DK061739, and R01DK079392 to C.A.P.). Additional support came from a Georgia Cancer Coalition Award (now the Georgia Research Alliance).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors declare that they have no conflicts of interest with the contents of this article.
About Beth Israel Deaconess Medical Center
Beth Israel Deaconess Medical Center is a leading academic medical center, where extraordinary care is supported by high-quality education and research. BIDMC is a teaching affiliate of Harvard Medical School, and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is the official hospital of the Boston Red Sox.
Beth Israel Deaconess Medical Center is a part of Beth Israel Lahey Health, a healthcare system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, more than 4,700 physicians and 39,000 employees in a shared mission to expand access to great care and advance the science and practice of medicine through groundbreaking research and education.
