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Basement membrane stiffness determines metastases formation

Reuten, Raphael ; Zendehroud, Sina ; Nicolau, Monica ; Fleischhauer, Lutz ; Laitala, Anu ; Kiderlen, Stefanie ; Nikodemus, Denise ; Wullkopf, Lena ; Nielsen, Sebastian Rune and McNeilly, Sarah , et al. (2021) In Nature Materials
Abstract
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... (More)
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. (Less)
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@article{11ec79d7-c0cf-4151-9c92-7ccb18f3af49,
  abstract     = {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.},
  author       = {Reuten, Raphael and Zendehroud, Sina and Nicolau, Monica and Fleischhauer, Lutz and Laitala, Anu and Kiderlen, Stefanie and Nikodemus, Denise and Wullkopf, Lena and Nielsen, Sebastian Rune and McNeilly, Sarah and Prein, Carina and Rafaeva, Maria and Schoof, Erwin M. and Furtwängler, Benjamin and Porse, Bo T. and Kim, Hyobin and Won, Kyoung Jae and Sudhop, Stefanie and Zornhagen, Kamilla Westarp and Suhr, Frank and Maniati, Eleni and Pearce, Oliver M. T. and Koch, Manuel and Oddershede, Lene Broeng and Van Agtmael, Tom and Madsen, Chris D. and Mayorca-Guiliani, Alejandro E. and Bloch, Wilhelm and Netz, Roland R. and Clausen-Schaumann, Hauke and Erler, Janine T.},
  issn         = {1476-4660},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Nature Materials},
  title        = {Basement membrane stiffness determines metastases formation},
  url          = {http://dx.doi.org/10.1038/s41563-020-00894-0},
  doi          = {10.1038/s41563-020-00894-0},
  year         = {2021},
}