David Sabatini - Biologists identify brain tumor weakness
Discovery could offer a new target for treatment of glioblastoma.
Anne Trafton | MIT News Office
April 8, 2015
at MIT and the Whitehead Institute have discovered a vulnerability of
brain cancer cells that could be exploited to develop more-effective
drugs against brain tumors.
The study, led by researchers from the Whitehead Institute and MIT’s
Koch Institute for Integrative Cancer Research, found that a subset of
glioblastoma tumor cells is dependent on a particular enzyme that breaks
down the amino acid glycine. Without this enzyme, toxic metabolic
byproducts build up inside the tumor cells, and they die.
Blocking this enzyme in glioblastoma cells could offer a new way to
combat such tumors, says Dohoon Kim, a postdoc at the Whitehead
Institute and lead author of the study, which appears in the April 8
online edition of Nature.
David Sabatini, a professor of biology at MIT and member of the
Whitehead Institute, is the paper’s senior author. Matthew Vander
Heiden, the Eisen and Chang Career Development Associate Professor of
Biology and a member of the Koch Institute, also contributed to the
research, along with members of his lab.
GLDC caught the researchers’ attention as they investigated diseases
known as “inborn errors of metabolism,” which occur when cells are
missing certain metabolic enzymes. Many of these disorders specifically
affect brain development; the most common of these is phenylketonuria,
marked by an inability to break down the amino acid phenylalanine. Such
patients must avoid eating phenylalanine to prevent problems such as
intellectual disability and seizures.
Loss of GLDC produces a disorder called nonketotic hyperglycinemia,
which causes glycine to build up in the brain and can lead to severe
mental retardation. GLDC is also often overactive in certain cells of
glioblastoma, the most common and most aggressive type of brain tumor
found in humans.
The researchers found that GLDC, which breaks down the amino acid
glycine, is overexpressed only in glioblastoma cells that also have high
levels of a gene called SHMT2, which converts the amino acid serine
into glycine. Those cells are so dependent on GLDC that when they lose
it, they die.
Further investigation revealed that SHMT2 is expressed most highly in
cancer cells that live in so-called ischemic regions — areas that are
very low in oxygen and nutrients. These regions are often found at the
center of tumors, which are inaccessible to blood vessels. It turns out
that in this low-oxygen environment, SHMT2 gives cells a survival edge
because it can indirectly influence the activity of an enzyme called
PKM2, which is part of the cell’s machinery for breaking down glucose.
Regulation of PKM2 can impact whether cells can generate the material
to build new cancer cells, but the same regulation also affects the
consumption of oxygen — a scarce resource in ischemic regions.
“Cells that have high SHMT2 activity have low PKM2 activity, and
consequently low oxygen-consumption rates, which makes them better
suited to survive in the ischemic tumor microenvironment,” Kim says.
However, this highly active SHMT2 also produces a glut of glycine,
which the cell must break down using GLDC. Without GLDC, glycine enters a
different metabolic pathway that generates toxic products that
accumulate and kill the cell.
“An interesting aspect of the current study is that they uncovered
why glycine accumulation is toxic,” says Navdeep Chandel, a professor of
medicine and cellular biology at Northwestern University who was not
part of the research team. “GLDC loss accumulates glycine, causing
nonketotic hyperglycinaemia, a disorder that severely affects the
developing brain. Sabatini and colleagues elucidated that loss of GLDC
builds up glycine levels, resulting in funneling of glycine into
metabolic pathways that generate toxic molecules, such as aminoacetone
The finding also raises the possibility that these GLDC-dependent
cells could be killed with drugs that block GLDC activity, according to
the researchers, who are now seeking potential drug compounds that could
do just that.
The research was funded by the American Brain Tumor Association, the National Institutes of Health, and the Koch Institute.