The research team used the Swiss Light Source for establishing the
structure of a receptor that plays a crucial role in cancer cell migration. The
Swiss Light Source is a synchrotron that is located at the Paul Scherrer
Institute in Switzerland. It is used for producing electromagnetic radiation
having high brightness. Elucidating the receptor structure enabled the
researchers to look for agents that could be used to halt cancer metastasis.
The study, published in the journal Cell
, was led by Dr. Jörg Standfuss,
PhD, who is the Group Leader of the Laboratory of Biomolecular Research at the
Paul Scherrer Institute in Villigen, Switzerland.
The lead author of the paper was Dr.
Steffen Brünle, PhD, who is a Postdoctoral Fellow in the Laboratory of
Biomolecular Research, working under Standfuss.
What is the Molecular Basis of
The process of
spreading of cancer cells
from the primary site
of development to distant secondary sites elsewhere in the body is termed as
metastasis. Once metastasis occurs, it kills almost 90 percent of cancer
patients. Metastatic cancer cells
often spread through the
lymphatic vessels, which are similar to blood vessels and form an elaborate
network throughout the body.
The cells of the
lymphoid tissues express a membrane protein known as C-C Chemokine Receptor Type 7
on their surface. CCR7 is involved in signal transduction, meaning that
it transfers external signals to the interior of the cell.
There are over 20
different chemokine receptors in the cells of all vertebrates that are capable
of interacting with over 40 chemokines, which are signaling proteins. Each
chemokine binds to its specific cell surface receptor and triggers the
signaling cascade that delivers the external signals to the interior of the
cell. This elicits a specific cellular response to the signal.
is an important cell surface chemokine receptor
responsible for cell movement within the body. Upon binding of the specific chemokine
to CCR7 on the cell membrane, a chain reaction is set into motion which causes
the cell to migrate in the direction of the highest concentration of the
chemokine. This mechanism is involved in the migration of lymphocytes (cells of
the immune system) to various lymph nodes located throughout the lymphatic
This same mechanism
can be exploited by cancer cells to migrate to other parts of the body during
the process of metastasis, so that they form tumors at distant secondary sites.
How was the Structure of CCR7
The structure of
CCR7 was deciphered through a joint collaborative effort between researchers at
the Paul Scherrer Institute and F. Hoffmann-La Roche. This laid the foundation
for developing a drug that could potentially prevent metastatic spread of
cancer cells in certain types of cancer such as colorectal cancer
utilized by the researchers to decipher the structure of CCR7 involved X-ray
crystallography at the Swiss Light Source located at the Paul Scherrer
structure of CCR7 was vital for initiating efforts to identify a suitable CCR7
"The right molecule can
prevent the signaling protein from coupling to the receptor and causing a
reaction in the cell",
structure of the receptor was a real challenge. The difficult thing about it was producing them, in the first place, in
such a way that we could examine them with X-ray crystallography",
Standfuss, co-leader of the Time-Resolved Crystallography Research Group at the
Paul Scherrer Institute.
In order to expedite the research, F. Hoffmann-La Roche
developed protein-modifying technology modules, known as crystallization
was the CCR7 Inhibitor Identified?
Deciphering the structure of CCR7 enabled the researchers to
quickly indentify a suitable inhibitor that blocked the receptor, thereby
preventing the initiation of the signaling cascade.
"Our experiments show
that the artificial molecule, inside the cell, binds to the receptor. This
keeps the chain reaction that leads to cell migration from getting started",
Search for the ideal inhibitor involved screening millions of
potential drug molecules deposited in the database at F. Hoffmann-La Roche.
X-ray crystallographic data of the drug-bound receptor, coupled with computer
simulation, enabled the identification of the best-fitting molecule that could
act as an inhibitor of CCR7. In fact, five such molecules were identified,
which are being taken forward for further development as potential anticancer drugs
Prospects of the New Discovery
This discovery will facilitate the development of a new class
of anticancer drugs that are capable of preventing metastasis. In fact, one of
the potential drug candidates has already entered human clinical trials, which
means that a new drug against cancer metastasis could soon be available.
- Structural Basis for Allosteric Ligand Recognition in the Human CC Chemokine Receptor 7 - (http://dx.doi.org/10.1016/j.cell.2019.07.028)