Cosmc converter

Cancer biologists are constantly hunting for tumor-specific antigens that can be targeted for monoclonal antibody therapy. Work by Andrea Schietinger, Mary Philip, Hans Schreiber, and colleagues (University of Chicago, IL) reveals that you don't need a mutation in the antigen itself to make it tumor specific. Incorrect posttranslational modification will do.

The group identified a mutation-free antigen in a spontaneous murine fibrosarcoma, called Ag104A. Mice with this tumor produce a high-affinity, highly specific antibody against what the group now identifies as a transmembrane protein called OTS8. Although OTS8 is widely expressed, the antibody was only reactive to OTS8 from the Ag104A tumor.

Tumor-derived OTS8 was a different molecular weight than its nonantigenic counterpart yet, to the group's surprise, was not mutated. The different molecular weight was instead due to altered glycosylation. Whereas normal OTS8 contained large sugar moieties, tumor-derived OTS8 predominantly contained a smaller monosaccharide called Tn. This novel combination of Tn and OTS8 created the tumor-specific antigen. The defective glycosylation was due to a mutation in a chaperone protein called Cosmc, which controls the activity of a galactosyltransferase enzyme.

A single mutation that leads to defective glycosylation provides the potential for multiple possible antigens, and, encouragingly, Cosmc mutations do not appear to be limited to just one type of tumor. In addition to previously identified Cosmc mutations in a human colon cancer and a T cell leukemia cell line, the team discovered that Cosmc was also mutated in a murine neuroblastoma that also overexpressed Tn.

Certain human cancers are known to overexpress Tn. If patients with these cancers have Cosmc mutations, it would strongly suggest that the tumor cells express many incorrectly glycosylated proteins that are potential tumor-specific targets for therapy.

Reference: