Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene variation promotes uncontrolled cell division

18.12.2015

Mom’s eyes and dad’s tumor? Cancer is due to genetic defects, some of which can be hereditary. The gene variant rs351855, for example, occurs in one in two cancer patients. A team headed by Axel Ullrich from the Max Planck Institute of Biochemistry in Martinsried identified the gene variant a decade ago. Now, they succeeded for the first time in showing that the variation exposes an otherwise hidden binding site on the FGFR4 receptor. There, growth factor STAT3, which promotes cancer, binds to the exposed site. The STAT3 signaling cascade can be efficiently blocked. This could provide a promising therapeutic approach for many cancer patients. The paper was published in Nature.

A human is a human: we are all 99.9% genetically identical. However, the remaining 0.1% accounts for the unique characteristics of each individual, whether he or she is tall or short, allergic or susceptible to autoimmune diseases. Those three million or so of the 3.2 billion genetic building blocks in our genome may contain the answer to the question of whether we will develop cancer in the course of our lives.


About 30% of the world population harbors the gene variation rs351855-A in their genomes. In the event of cancer, the encoded receptor FGFR4 p.G388R contributes to a faster disease progression.

Vijay K. Ulaganathan, Monika Krause © MPI of Biochemistry

Cancer is a genetic disease, i.e. it is due to defects in the genetic material DNA. Such harmful mutations can be acquired in the course of life, as a result of exposure of skin cells to intense sunlight, for example, or toxins from cigarette smoke in the lungs. However, some defects are passed on as inheritable genetic variants to offspring, who then carry those defects in every cell of their body.

One such cancer-associated germline mutation is called rs351855. It was discovered in patients with breast cancer by a team headed by Axel Ullrich, Leader of the Molecular Biology Research Group, a decade ago. This particular genetic variant can support the growth of malignant tumors in bones, the colon, the prostate, the skin, the lungs and the head and neck, as well as to the growth of soft-tissue sarcomas and non-Hodgkin’s lymphoma.

About half of all cancer patients carry this gene variation. It is associated with a poor prognosis. The germline mutation rs351855 accounts for aggressive and rapidly growing tumors that are resistant to treatment. An effective treatment needs to be tailored to match the mutation and its biological effects.

Subsequent studies have shown that rs351855 results in the replacement of a single protein building unit in a receptor for growth factors. Fibroblast growth factor receptor 4 (FGFR4) is then expressed in the form of the FGFR4 p.Arg388 variant. Scientists around the world are trying to find out why only this particular genetic variant, out of more than 400 known ones of FGFR4, has such a high impact. Moreover, the genetic mutation occurs very frequently, around one-third of the population carry it in the genome. It is not known, whether this variation itself increases the general risk of cancer.

Ullrich and his associates have now demonstrated for the first time that the defect results in a previously unknown biological function in living cells. They showed in an animal model that the defect exposes a normally hidden binding site on the receptor molecule near the inner cell membrane. Growth factor STAT3, which promotes cell division and tumor growth, is then able to dock to the receptor.

Cells do not usually proliferate out of control, because they only divide in response to a signal that they receive from the outside. This molecular message is picked up by receptors such as FGFR4 and is then relayed through the cell membrane into the interior of the cell, thus setting in motion a cascade of molecular interactions with molecules such as STAT3 that culminates in the cell nucleus, where genes are activated that direct the actual process of cell division.

This hierarchical process is often undermined in cancer. The cells divide without an external command. That is the case, for example, when STAT3 is activated by abnormal binding to the defective receptor. Such interaction of STAT3 close to the inner cell membrane was previously unknown and unexpected. “I wasn’t really convinced until various experimental approaches produced matching results,” says Vijay K. Ulaganathan, lead author of the study.

The scientists have also shown that the growth of cells carrying this gene variant can be inhibited by blocking STAT3. “For the first time, there may be very good prospects of an effective treatment option for cancer patients with this respective germline mutation,” says Ullrich. Others may also be affected: Other germline mutations also exist that recruit STAT3 to the inner cell membrane and may also lead to cancer.

The work is an important step towards personalized medicine, which takes into account the individual genetic makeup of cancer patients. “As we have shown here, we need to focus on germline mutations as well,” says Ullrich. “Research should not be limited to environmentally-related genetic defects.” Ullrich is a pioneer in personalized medicine. Among other things, he developed together with colleagues Herceptin, a drug that is tailor-made for treating breast cancer associated with specific mutations.

Original publication:
V. K. Ulaganathan, B. Sperl, U. R. Rapp, Axel Ullrich: Germline variant FGFR4 p.G388R exposes membrane-proximal STAT3 binding site, Nature, December 2015
DOI: 10.1038/nature16449

Contact:
Prof. Dr. Axel Ullrich
Department of Molecular Biology
Max-Planck-Institut für Biochemie
Am Klopferspitz 18
82152 Martinsried
Germany
E-Mail: ullrich@biochem.mpg.de
www.biochem.mpg.de/ullrich

Dr. Vijay K. Ulaganathan
Department of Molecular Biology
Max-Planck-Institut für Biochemie
Am Klopferspitz 18
82152 Martinsried
Germany
E-Mail: ulaganat@biochem.mpg.de

Dr. Christiane Menzfeld
Public Relations
Max-Planck-Institut für Biochemie
Am Klopferspitz 18
82152 Martinsried
Germany
Tel. +49 89 8578-2824
E-Mail: pr@biochem.mpg.de
www.biochem.mpg.de

Weitere Informationen:

http://www.biochem.mpg.de - homepage max planck institute of biochemistry
http://www.biochem.mpg.de/ullrich - homepage Axel Ullrich

Dr. Christiane Menzfeld | Max-Planck-Institut für Biochemie

More articles from Life Sciences:

nachricht A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Multicrystalline Silicon Solar Cell with 21.9 % Efficiency: Fraunhofer ISE Again Holds World Record

20.02.2017 | Power and Electrical Engineering

Biocompatible 3-D tracking system has potential to improve robot-assisted surgery

17.02.2017 | Medical Engineering

Real-time MRI analysis powered by supercomputers

17.02.2017 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>