The FAKs of Metastasis
By Jason Socrates
Bardi
"I
immediately considered that this must be some ship in distress,
and that they had some comrade, or some other ship in company,
and fired these for signals of distress... to obtain help."
——Daniel
Defoe, Robinson Crusoe, 1719.
A psychologist who specializes in the dynamics of small groups
of people might say that within any such small group, one
of the most important traits for building and maintaining
good interpersonal relationships is empathy—understanding,
being aware of, having sensitivity to, and otherwise fully
communicating with one another.
There are parallels in the way cells interact. While biological
molecules don't use empathy, they do communicate among themselves
during cell signaling, using their own set of subtle and intricate
signals.
David Schlaepfer, associate professor in the Department
of Immunology at The Scripps Research Institute (TSRI), has
an appreciation for these interactions are their complex nature.
He studies an intricate group of signaling molecules involved
in cell motility and cancer. In particular, he investigates
how certain cues can cause epithelial cells, which cover most
inner and outer “surfaces” in the body, to move
when they are cancerous.
“All the players [responsible for this] are not known,”
says Schlaepfer.
Just the FAKs
However, it is known that a protein called focal adhesion
kinase (FAK), a large, important signaling molecule of about
120,000 daltons, is involved in cancer as well as a variety
of other roles in the body. FAK is an enzyme that attaches
phosphate groups to tyrosine residues on other target proteins
inside cells, thereby modulating their function.
As its name suggests, FAK is involved in the regulation
of focal adhesion formation—the physiological phenomenon
whereby cells attach to a scaffold-like arrangement of sugars,
proteins, collagens, and other molecules forming the extracellular
matrix. The extracellular matrix is a cementing agent that
holds cells together and maintains tissue architecture.
“In addition,” says Satyajit Mitra, a postdoctoral
fellow in Schlaepfer’s laboratory, “FAK is important
for turning over focal adhesions.” FAK does not form
focal adhesions, Mitra adds, but what it does is turn them
over rapidly. In the absence of FAK, cells get stuck because
they have more focal adhesions with the extracellular matrix
and stronger ones, too.
Cells attach to the extracellular matrix through proteins
on their surface called integrins. Integrins are cell surface
receptors that transduce survival, angiogenesis, motility,
and positional cues. To deliver these signals, integrins recruit
a large assembly of signaling proteins, with FAK as a key
and central component.
However, FAK is not merely an interesting protein that one
might encounter occasionally in the scientific literature.
FAK, because of its role as a regulator of focal adhesion
turnover and cell motility, is also highly important in cancer
and the worst kind of tumor cell growth.
“In clinical settings,” says Schlaepfer, “the
expression of FAK is tightly correlated with increased human
tumor cell metastasis.”
FAK and Cancer
Cancer is the second leading cause of death in the United
States, claiming over 500,000 lives and costing over $100
billion in healthcare and related costs every year, according
to the Centers for Disease Control and Prevention.
The role of basic science in this context is to understand
cancer—to understand how normal, healthy cells can mutate
into dangerous changelings.
These transformations often lead the cells to acquire abilities
that they did not have before. The ability to stay alive and
divide over and over, forming a tumor, for example, is not
something normal cells do. Nor is the ability of a cell that
is normally fixed in one place in one tissue of the body to
get up and move through the bloodstream, anchor down in a
distant tissue, and begin a new cancer—in other words,
to metastasize.
Metastasis is a dangerous phenomenon through which many
cancers are able to claim lives by spreading to multiple tissues
and organs and compromising their function. While surgeons
can remove cancerous tissue, such procedures are greatly complicated
if a tumor establishes new tumors in other tissues, a process
known as metastasis. One of the aims of basic science is to
elucidate the mechanism of and find ways to deal with cancer
metastasis.
Metastasis depends on the cancerous cells acquiring two
separate abilities—increased motility and invasiveness.
Motility, the ability of a cell to get up and go, is an obvious
requirement for metastasis. The word “metastasis”
comes from the Latin construction meaning to change position.
Perhaps not so obvious is the need for cancerous cells to
invade tissue, to burrow in and set up shop somewhere else.
Invasion is the completion and therefore a requirement for
metastasis.
These “phenotypic” abilities do not arise out
of thin air. Cancerous cells acquire them in part through
mutations to their DNA that result in changes of expression
of one or more genes. Often as these expression levels change,
so do the levels of other, related genes.
Schlaepfer and his colleagues are specifically interested
in the role that FAK plays in all of this and they are trying
to get at these mechanisms in tumor cells to see if they can
intervene in that process.
Methods for Studying FAK
Schlaepfer and his laboratory have been asking several questions
related to FAK, including, on the most basic level, what role
it plays in tumors.
Tumors over-expressing FAK are larger, have a significant
advantage for growth, and have a cunning ability to invade
new tissue. “We have found that tumor cells lacking FAK
don’t metatasize and we can re-initiate this process
by genetically re-expressing FAK in these cells,” says
Schlaepfer.
Schlaepfer and his colleagues are using a set of cell culture
assays and in vivo models to tease apart the role
of FAK in different cells and under different conditions.
They compared the gene expression profile in tumor cells that
do not express FAK, those that do, and those that have been
“reconstituted” by putting FAK expression back in
to discover its properties.
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Associate
Professor David Schlaepfer (center) and his laboratory have
been asking several questions related to the signaling molecule
FAK, including what role it plays in tumors. Other lab members
include (left to right) Satyajit K. Mitra, John E. Molina,
and Datsun A. Hsia.