First step towards early diagnosis of metastases

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Stiff basement membranes promote metastasis. Image: Ella Maru Studios
Stiff basement membranes promote metastasis. Image: Ella Maru Studios

Team involving the University of Freiburg has developed a new method for analyzing the basement membrane in the human lung

Metastases are largely responsible for the mortality of patients with solid cancers; the prognosis of cancer patients is significantly reduced when metastases are diagnosed. To date, there are no methods that allow a reliable prediction of the probability of future metastases. A team of scientists from Denmark and Germany led by Raphael Reuten from the Faculty of Medicine at the University of Freiburg and Hauke Clausen-Schaumann from Munich University of Applied Sciences has now succeeded in taking a first step towards early diagnosis: They developed a user-friendly method for analyzing the so-called basement membrane in the human body- because its mechanical properties are a decisive factor in the metastasis of cancer cells. The results were published in the renowned journal Nature Protocols.

Softer basement membrane is more difficult to overcome

"We are convinced that the publication of this method in the form of a detailed protocol will make it possible to come closer to an early diagnosis of metastases," says Reuten. With the protocol, scientists worldwide could show that different individuals have different basement membrane mechanics and how these are related to metastasis formation. The basement membrane is a structure of the extracellular matrix - i.e. of proteins outside the cells - that coats all blood vessels, many organs and also tumors.

In the past, it was assumed that this structure was merely an obstacle that cancer cells had to overcome with the help of their own mechanisms. However, in a paper published in 2021, Reuten and Clausen-Schaumann were able to show that the mechanical property of the basement membrane is a decisive factor that influences the metastasis of cancer cells and thus also the prognosis of cancer patients: the softer the basement membrane is, the fewer cancer cells overcome this obstacle - fewer metastases form.

Evaluation using semi-automated software

Together with the Department of Gynecology at the University Medical Center Freiburg and the Department of Pathology at Rigshospitalet Copenhagen, the scientists have now published a measurement protocol in the form of a detailed and user-friendly step-by-step guide that can be used to determine the mechanical properties of the basement membrane in the human lung. The team is also providing the scientific community with semi-automated software for evaluating the measurement data and identifying the basement membrane, which is to be made even more powerful in the future using artificial intelligence: "As soon as more extensive data material is available, fully automated recognition of the basement membrane using machine learning is to be implemented," says the first author of the study, Bastian Hartmann from Munich University of Applied Sciences.

The basement membrane has a thickness of only around 100 to 400 nanometers (about one ten-thousandth of a millimeter). "It was a particular challenge to localize it exactly in the tissue, to measure its mechanical properties and to separate them precisely from those of the surrounding tissue," says biophysicist Hauke Clausen-Schaumann. "We were able to solve this using a combination of optical microscopy and atomic force microscopy." The new protocol now extends this method to the basement membrane of the human lung and makes it easier to use.

Further insights for cancer research

The scientists expect to gain important insights for cancer research from the data that can be obtained using this method. Although tumors remodel many structures in the body to meet the needs of cancer cells, the individual mechanical properties of the basement membrane have an important influence on the metastasis process, regardless of such cancer-related changes. It could therefore be, Reuten suspects, that certain mechanics of the basement membrane make some people more susceptible to metastases in principle.

Overview of facts:

    Original publication: Bastian Hartmann, Lutz Fleischhauer, Monica Nicolau, Thomas Hartvig Lindkær Jensen, Florin-Andrei Taran, Hauke Clausen-Schaumann, Raphael Reuten: Profiling native pulmonary basement membrane stiffness using atomic force microscopy. In: Nature Protocols
    DOI:­’024 -00955-7

  • Dr. Raphael Reuten has been a junior professor at the Institute of Experimental and Clinical Pharmacology and Toxicology at the University of Freiburg since mid-2021 and heads a research group, the MatriTecture Lab for Functional Biochemistry. His focus is on the influence of extracellular architecture on cellular processes with a focus on tumor progression - with the aim of bringing extracellular matrix-based diagnostic and therapeutic strategies into clinical application.
  • Hauke Clausen-Schaumann conducts research at the Center for Applied Tissue Engineering and Regenerative Medicine at Munich University of Applied Sciences. He specializes in determining the mechanical properties of biomaterials on the nanometer scale. Bastian Hartmann is a doctoral student in Clausen-Schaumann’s working group, focusing on nanomechanical investigations of tissue using the atomic force microscope.
  • The project was funded by the Bavarian State Ministry of Science and the Arts and the Bavarian Science Forum (BayWISS), the German Research Foundation (DFG) and the Danish Cancer Society.