Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Pancreatic cancer: Gene duplication explains tumor aggressiveness

30.01.2018

Pancreatic cancer is a form of cancer associated with the highest mortality rates in the world. However, until now genetic changes that could explain the aggressiveness and early metastasis of this form of cancer had not been found. A team of researchers at the Technical University of Munich (TUM) and the German Cancer Consortium (DKTK) has now shown that those characteristics can be explained by specific gene amplifications which occur along various evolutionary pathways of the cancer. Based on this discovery, they have derived basic principles underlying the biology of this cancer type.

Until now, scientists have failed to establish a link between the properties of pancreatic cancer, such as its aggressiveness, and changes, i.e. mutations, in the tumor’s genome. Moreover, pancreatic cancer forms metastases much faster than other types of cancer. Here too, the genetic causes are unclear.


The research of Roland Rad and his team ist focused on molecular and translational aspects of cancer development.

A. Heddergott / Technical University of Munich

A team headed by Professor Roland Rad and Professor Dieter Saur of TUM University Hospital rechts der Isar and the German Cancer Consortium has taken an important step towards solving both mysteries.

With the help of various mouse models for pancreatic cancer, they have succeeded in elucidating the molecular pathways of tumor development in detail and have gained a better understanding of how various characteristics of the disease arise. The study was published in the journal Nature.

Tumor cells have multiple defective copies of a cancer gene

Healthy cells in humans possess two copies of each gene. For their experiments, the researchers mutated one of the two copies of the KRAS gene in mice. The gene plays a key role in cellular proliferation and is activated in 90% of all human pancreatic tumors.

Such genes are referred to as oncogenes. The team headed by Roland Rad made a surprising discovery: The mutant gene was often duplicated even in very early stages of the cancer. In cases where a tumor had not doubled the mutated KRAS gene copy, the researchers discovered duplications in other cancer genes.

“It therefore appears that the cell amplifies the growth signal due to the presence of extra gene copies. This model of dosage amplification during tumor development had not previously been considered,” says Sebastian Müller, lead author of the study. “We also showed that as the number of mutant KRAS copies increases, the tumor’s aggressiveness and ability to metastasize also increases.”

Disruption of endogenous protective mechanisms determines the evolution of the cancer

Normally, healthy cells have their own protective mechanisms to prevent mutations from accumulating. So how could the cells develop such dosage amplification without being prevented from doing so?

“This shows the importance of mouse models, which allow us to closely observe and experimentally review the extraordinarily complex processes of cancer development at the molecular level: from healthy cells to cancer precursors through to aggressive tumors and their spread to other organs,” Professor Dieter Saur explains.

After the KRAS mutation was induced by the researchers, other mutations in what are known as tumor suppressor genes developed. A healthy cell possesses a whole series of such protective genes to prevent cancer from developing. A significant finding by the team was that either the mutant KRAS gene or another cancer gene is amplified, depending on which tumor suppressor gene is affected and to what degree its function is impaired.

Key developmental stages explained

Only after the cell's inbuilt protective mechanisms have been switched off and dosage amplification occurs does a tumor ultimately form. Which pathway the cell follows, and which genes are involved then largely determine the characteristics of a pancreatic tumor.

For the first time, the dosage amplification model allows us to identify genetic patterns that explain a tumor’s aggressiveness and metastasis. “We have indications that our discovery constitutes a fundamental principle in the development of tumors and plays an essential role in other cancers. We’re now investigating the extent to which these new insights into cancer biology can be used to develop new therapeutic strategies,” says Professor Roland Rad, explaining the team’s next research goals.


The following institutions contributed to the study: Technical University of Munich (Central Institute of Translational Cancer Research, Clinic and Policlinic for Internal Medicine II, Institute of Pathology), DKTK and DKZF Heidelberg; The Wellcome Trust Sanger Institute, Cambridge; Ludwig-Maximilians Universität (Anthropology & Human Genomics und Innere Medizin II des Klinikums Großhadern), Helmholtz Zentrum München (Research Unit Radiation Cytogenetics); Universidad de Oviedo (Bioquímica y Biología Molecular, IUOPA und CINN-CSIC), Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, University of Cambridge (Department of Veterinary Medicine), Instituto de Medicina Oncológica y Molecular de Asturias, Instituto de Biomedicina y Biotecnología de Cantabria.

Original publication
S. Mueller, T. Engleitner, R. Maresch, M. Zukowska, S. Lange, T. Kaltenbacher, B. Konukiewitz, R. Öllinger, M. Zwiebel, A. Strong, H.-Y. Yen, R. Banerjee, S. Louzada, B. Fu, B. Seidler, J. Götzfried, K. Schuck, Z. Hassan, A. Arbeiter, N. Schönhuber, S. Klein, C. Veltkamp, M. Friedrich, L. Rad, M. Barenboim, C. Ziegenhain, J. Hess, O. M. Dovey, S. Eser, S. Parekh, F. Constantino-Casas, J. de la Rosa, M. I. Sierra, M. Fraga, J. Mayerle, G. Klöppel, J. Cadiñanos, P. Liu, G. Vassiliou, W. Weichert, K. Steiger, W. Enard, R. M. Schmid, F. Yang, K. Unger, G. Schneider, I. Varela, A. Bradley, D. Saur, R. Rad, Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes, Nature, 201, DOI: 10.1038/nature25459
https://www.nature.com/articles/nature25459

Contact
Prof. Dr. med. Roland Rad
Clinic and Policlinic for Internal Medicine II
University Hospital rechts der Isar of the Technical University of Munich
Tel.: (0 89) 41 40 - 43 74
Email: roland.rad@tum.de

www.tum.de

Weitere Informationen:

http://www.tum.de/nc/en/about-tum/news/press-releases/detail/article/34426/ - This text on the web
https://www.tum.de/en/about-tum/news/ - All press releases of the Technical University of Munich
https://www.med2.mri.tum.de/en/research/ag-rad.php - Research Group of Roland Rad
https://www.med2.mri.tum.de/en/research/ag-saur.php# - Research Group of Dieter Saur

Dr. Ulrich Marsch | Technische Universität München

More articles from Health and Medicine:

nachricht Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University

nachricht Direct conversion of non-neuronal cells into nerve cells
03.07.2018 | Universitätsmedizin der Johannes Gutenberg-Universität Mainz

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Microscopic trampoline may help create networks of quantum computers

17.07.2018 | Information Technology

In borophene, boundaries are no barrier

17.07.2018 | Materials Sciences

The role of Sodium for the Enhancement of Solar Cells

17.07.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>