Reuten, Raphael ORCID: 0000-0002-9434-4108, Zendehroud, Sina ORCID: 0000-0002-5822-722X, Nicolau, Monica, Fleischhauer, Lutz ORCID: 0000-0002-0234-5446, Laitala, Anu, Kiderlen, Stefanie, Nikodemus, Denise, Wullkopf, Lena, Nielsen, Sebastian Rune ORCID: 0000-0002-8449-476X, McNeilly, Sarah, Prein, Carina, Rafaeva, Maria ORCID: 0000-0002-7317-4058, Schoof, Erwin M., Furtwangler, Benjamin ORCID: 0000-0002-5884-3380, Porse, Bo T., Kim, Hyobin ORCID: 0000-0002-4856-7415, Won, Kyoung Jae, Sudhop, Stefanie ORCID: 0000-0002-0838-9503, Zornhagen, Kamilla Westarp, Suhr, Frank ORCID: 0000-0002-9013-3944, Maniati, Eleni, Pearce, Oliver M. T., Koch, Manuel ORCID: 0000-0002-2962-7814, Oddershede, Lene Broeng, Van Agtmael, Tom ORCID: 0000-0003-4282-449X, Madsen, Chris D., Mayorca-Guiliani, Alejandro E., Bloch, Wilhelm, Netz, Roland R., Clausen-Schaumann, Hauke ORCID: 0000-0002-9413-0310 and Erler, Janine T. (2021). Basement membrane stiffness determines metastases formation. Nat. Mater., 20 (6). S. 892 - 927. BERLIN: NATURE RESEARCH. ISSN 1476-4660

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Abstract

The basement membrane stiffness is shown to be a more dominant determinant than pore size in regulating cancer cell invasion, metastasis formation and patient survival. This stiffness is now known to be affected by the ratio of netrin-4 to laminin, with more netrin-4 leading to softer basement membranes. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Reuten, RaphaelUNSPECIFIEDorcid.org/0000-0002-9434-4108UNSPECIFIED
Zendehroud, SinaUNSPECIFIEDorcid.org/0000-0002-5822-722XUNSPECIFIED
Nicolau, MonicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fleischhauer, LutzUNSPECIFIEDorcid.org/0000-0002-0234-5446UNSPECIFIED
Laitala, AnuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kiderlen, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikodemus, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wullkopf, LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, Sebastian RuneUNSPECIFIEDorcid.org/0000-0002-8449-476XUNSPECIFIED
McNeilly, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prein, CarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rafaeva, MariaUNSPECIFIEDorcid.org/0000-0002-7317-4058UNSPECIFIED
Schoof, Erwin M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Furtwangler, BenjaminUNSPECIFIEDorcid.org/0000-0002-5884-3380UNSPECIFIED
Porse, Bo T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, HyobinUNSPECIFIEDorcid.org/0000-0002-4856-7415UNSPECIFIED
Won, Kyoung JaeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sudhop, StefanieUNSPECIFIEDorcid.org/0000-0002-0838-9503UNSPECIFIED
Zornhagen, Kamilla WestarpUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suhr, FrankUNSPECIFIEDorcid.org/0000-0002-9013-3944UNSPECIFIED
Maniati, EleniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pearce, Oliver M. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, ManuelUNSPECIFIEDorcid.org/0000-0002-2962-7814UNSPECIFIED
Oddershede, Lene BroengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Agtmael, TomUNSPECIFIEDorcid.org/0000-0003-4282-449XUNSPECIFIED
Madsen, Chris D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayorca-Guiliani, Alejandro E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloch, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Netz, Roland R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clausen-Schaumann, HaukeUNSPECIFIEDorcid.org/0000-0002-9413-0310UNSPECIFIED
Erler, Janine T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-602399
DOI: 10.1038/s41563-020-00894-0
Journal or Publication Title: Nat. Mater.
Volume: 20
Number: 6
Page Range: S. 892 - 927
Date: 2021
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 1476-4660
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BIOMECHANICAL PROPERTIES; MECHANICAL-PROPERTIES; CELL-PROLIFERATION; CANCER METASTASIS; GENE-EXPRESSION; BREAST-CANCER; NETRIN-4; IDENTIFICATION; LAMININ; MOUSEMultiple languages
Chemistry, Physical; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed MatterMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60239

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