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% of pediatric kidney cancers -
rhabdoid tumors are highly lethal with a survival rate of less than 25%.
Rhabdoid tumors are among the most recalcitrant childhood cancers,
and scientists have long sought ways to understand what drives their
resilience and makes them impervious to treatment.
‘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.’
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.
The report of the multi-institutional team's findings, published 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
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
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.
The curious case of the mutation-free tumor
Throughout the past decade, advances in cancer genome sequencing
have revealed cancer cells have very high rates of genetic mutations.
This mutability turns tumors into shape-shifters capable of evading drug
therapies. But, curiously, rhabdoid tumors are among the most
genomically stable and least mutable of cancers, harboring only a few
genetic mutations, compared with the hundreds or thousands of mutations
in other cancers. So what exactly makes these immutable tumors so
pernicious, the researchers wondered?
Based on the study's findings, the answer appears to
lie - literally - outside of the tumor cell's DNA and in its
epigenome--the separate layer of proteins and chemical modifiers that
sits atop DNA and can profoundly alter its behavior.
Cancer's survival kit
The insights illuminate a critical survival mechanism that allows rhabdoid tumors to escape the body's checks and controls.
In a series of experiments with patient-derived rhabdoid tumor
tissue, the investigators showed that the absence of SMARCB1 interferes
with SWI/SNF's function. Researchers observed the lack of SMARCB1
dramatically reduced the levels of several other proteins that make up
the SWI/SNF complex, severely weakening its regulatory ability.
Specifically, SMARCB1 deletion interfered with the SWI/SNF's ability
to bind to genetic switches called enhancers - snippets of DNA that
act as genome regulators to determine which genes get turned on and
which ones remain dormant.
Some 10,000 to 20,000 enhancers are turned on in any given cell at
any given time. Because all cells in an organism share the same DNA, the
activity of these genetic switches is critical to determining which
genes in a cell get activated to produce what proteins. In other words,
enhancers play a vital role in determining the identity and behavior of a
Loss of SMARCB1, the experiments showed, led to the deactivation of
many of the regular enhancers that modulate gene expression and cell
behavior, while at the same time keeping another set of enhancers
switched on. The researchers think it is precisely those "on" enhancers
that may be critical to tumor growth and survival.
"If something goes wrong in deciding which enhancers should be on,
the cell loses its identity," said co-investigator Burak Han Alver, a
research associate in biomedical informatics at HMS who focuses on
epigenetic regulation and transcription. "When that happens, in most
cases, the cells will realize there is a problem and trigger self-death.
But, in rare cases, errors in the enhancer landscape can lead to
cancer. This is what we observed is happening in the case of rhabdoid
Finding a way to shut off the remaining active enhancers, the
researchers said, could turn out to be a chink in the armor of rhabdoid
tumors and provide a target for treatment.
In a final, proof-of-concept step, the scientists restored SMARCB1
inside cell lines derived from patient tumors. The tumor cell lines
stopped growing, a finding that underscores the protein's role in
curbing tumor formation, the team said.