Basement membrane stiffness determines metastases formation

Reuten, R. et al. (2021) Basement membrane stiffness determines metastases formation. Nature Materials, 20(6), pp. 892-903. (doi: 10.1038/s41563-020-00894-0) (PMID:33495631)

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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:Articles
Additional Information:This work was supported by the European Research Council (ERC-2015-CoG-682881-MATRICAN; RR, MN, AEM-G, and JTE); the Danish Cancer Society (R204-A12454; RR), (R146-A9250; AL), and (R167-A10618; SRN), the German Cancer Aid (RR); a Hallas Møller Stipend from the Novo Nordisk Foundation (JTE), the German Research Foundation (DFG) (NI 1895/1-1; DN), (CRC1114/C02; SZ and RRN), (FOR2722/B2; MK), and (CRC829; WB), a PhD fellowship from the Lundbeck Foundation (R286-2018-621; MR), a postdoctoral fellowship from the Lundbeck Foundation (R250-2017-389; EMS), a grant from the Novo Nordisk Foundation (Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, NNF17CC0027852; EMS, BTP, HK, and KJW; NNF19SA0035442, BF), the Danish Research Council (DFF-4002-00099; LW and LBO), an MRC (MR/R005567-1; TVA) and BHF (PG/15/92/31813; TVA), a BHF studentship (FS/15/64/32035; SM), CANTER Research Focus of the Bavarian State Ministry for Science and Education (LF, SK, CP, SS, and HCS), a CRUK fellowship (A27947; OMTP), the Ragnar Söderberg Foundation Sweden (N91/15; CDM), Swedish Research Council (2017-03389; CDM), Cancerfonden Sweden (CAN 2016/783, 19 0632 Pj and 190007; CDM), Åke Wiberg Foundation (M17-0235; CDM), and Crafoord Foundation (20171049; CDM).
Glasgow Author(s) Enlighten ID:Van Agtmael, Professor Tom
Authors: Reuten, R., Zendehroud, S., Nicolau, M., Fleischhauer, L., Laitala, A., Kiderlen, S., Nikodemus, D., Wullkopf, L., Nielsen, S. R., McNeilly, S., Prein, C., Rafaeva, M., Schoof, E. M., Furtwängler, B., Porse, B. T., Kim, H., Won, K. J., Sudhop, S., Westarp Zornhagen, K., Suhr, F., Maniati, E., Pearce, O. M.T., Koch, M., Oddershede, L. B., Van Agtmael, T., Madsen, C. D., Mayorca Guiliani, A. E., Bloch, W., Netz, R. R., Clausen-Schaumann, H., and Erler, J. T.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Nature Materials
Publisher:Nature Research
ISSN (Online):1476-4660
Published Online:25 January 2021
Copyright Holders:Copyright © 2021 Springer Nature
First Published:First published in Nature Materials 20(6): 892-903
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
302164Collagen IV variants and their role in intracerebral haemorrhage in the general populationTom Van AgtmaelMedical Research Council (MRC)MR/R005567/1CAMS - Cardiovascular Science
172813Targeting intracellular pathways to dissect mechanisms of cerebrovascular disease.Tom Van AgtmaelBritish Heart Foundation (BHF)PG/15/92/31813Institute of Cardiovascular & Medical Sciences
172199BHF 4 Year PhD Studentship Award (3rd intake 2015)Rhian TouyzBritish Heart Foundation (BHF)FS/15/64/32035Institute of Cardiovascular & Medical Sciences