Basement membrane stiffness determines metastases formation.

The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our biophysical and functional analyses in combination with mathematical simulations show that Net4 softens the mechanical properties of native BMs by opening laminin node complexes, decreasing cancer cell potential to transmigrate this barrier despite creating bigger pores. Our results therefore reveal that BM stiffness is dominant over pore size, and that the mechanical properties of 'normal' BMs determine metastases formation and patient survival independent of cancer-mediated alterations. Thus, identifying individual Net4 protein levels within native BMs in major metastatic organs may have the potential to define patient survival even before tumour formation. The ratio of Net4 to laminin molecules determines BM stiffness, such that the more Net4, the softer the BM, thereby decreasing cancer cell invasion activity.

Citation

Raphael Reuten, Sina Zendehroud, Monica Nicolau, Lutz Fleischhauer, Anu Laitala, Stefanie Kiderlen, Denise Nikodemus, Lena Wullkopf, Sebastian Rune Nielsen, Sarah McNeilly, Carina Prein, Maria Rafaeva, Erwin M Schoof, Benjamin Furtwängler, Bo T Porse, Hyobin Kim, Kyoung Jae Won, Stefanie Sudhop, Kamilla Westarp Zornhagen, Frank Suhr, Eleni Maniati, Oliver M T Pearce, Manuel Koch, Lene Broeng Oddershede, Tom Van Agtmael, Chris D Madsen, Alejandro E Mayorca-Guiliani, Wilhelm Bloch, Roland R Netz, Hauke Clausen-Schaumann, Janine T Erler. Basement membrane stiffness determines metastases formation. Nature materials. 2021 Jun;20(6):892-903

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PMID: 33495631

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