Agent of mischief

Now researchers from Harvard Medical School, St. Jude Children's Research Hospital and elsewhere have uncovered a molecular chain of events that interferes with a key mechanism that regulates cell behavior and controls tumor formation.

Rhabdoid tumors typically start out in the kidneys, but they can also arise or migrate into the brain and other soft tissues. While rare -- they account for less than 2 percent of pediatric kidney cancers -- rhabdoid tumors are highly lethal with a survival rate of less than 25 percent.

The report of the multi-institutional team's findings, published Dec. 12 in Nature Genetics, describes how the loss of a protein, SMARCB1, can disrupt the work of a regulatory mechanism, thereby fueling uncontrolled malignant cell proliferation and the continued survival of rhabdoid tumors.

The absence of SMARCB1 in rhabdoid tumor cells has been known for some time, so scientists suspected it played a role in cancer development. Yet, just how it did so remained somewhat of a puzzle.

The new findings provide the missing piece in that puzzle and reveal just how the absence of SMARCB1 unlocks a chain of events that culminates in the loss of cellular identity and profound aberrations in cell behavior.

SMARCB1 is a key component of a protein complex known as SWI/SNF, which largely acts as a tumor suppressor. SWI/SNF works by altering the packaging of genetic material inside a cell's nucleus. Such alterations are important because they make DNA accessible to proteins that turn on gene expression, a fundamental way to regulate cell behavior and determine cell identity.

"Our results shed light into the long-standing mystery of rhabdoid tumor behavior," said study co-senior author Peter Park, associate professor of biomedical Informatics at HMS. "They reveal just how SMARCB1 becomes the central character that unleashes mischief in a twisted plot of epigenetic changes that alter cell identity and fuel cancer formation."

The findings, the research team said, identify possible treatment targets and provide a conceptual framework for designing therapies.

In addition, the team said, the results may have relevance for other forms of cancer.

"Mutations in the SWI/SNF complex occur in a broad range of human cancers so our findings may provide insight well beyond rhabdoid tumors," said Charles Roberts, co-senior author and director of the Comprehensive Cancer Center at St. Jude.