AG Reuten
Contact: raphael.reuten[at]pharmakol.uni-freiburg.de
The extracellular matrix (ECM) is the non-cellular compartment of living organisms, which is divided into the two ECM subtypes: the interstitial matrix and the basement membrane (BM). The existence of multicellular organisms without the strcutural ECM would not be possible. Apart from providing the functional scaffold for an organism, cells interact and thereby communicate with the ECM through the formation of cell adhesion complexes (CAMs), mainly integrins located on the plasma membrane1, leading to the activation of signalling pathways that transduce outside-in cell signalling. Cells utilize a distinct set of CAMs to interact with different ECM macromolecules such as laminins, collagens, and fibronectin.
Decellularized tissue adjacent to the aorta, immunostained with rat anti-laminin γ1 (555 nm, cyan) and goat anti- collagen IV (647 nm, magenta) antibodies. Image modified from2.
To establish metastases in distant organs, cancer cells have to go through several successive steps known as the invasion-metastasis process. This multistep event causes 60-90% cancer-related deaths3,4 and is defined as the invasion-metastasis process: (i) invade through the basement membrane (BM)-lining the epithelium of origin and the tumor surrounding interstitial matrix (invasion), (ii) access lymphatic and endothelial vessels through breaching vascular BMs (intravasation), (iii) survive inside the blood stream and arrest at a distant organ, (iv) escape the blood stream through breaching vascular BMs (extravasation), (v) survive within the distant microenvironment, and (vi) proliferate and establish a cancer-related microenvironment (colonization)5,6 Cancer cells travel through the intercellular space by invading through the BM and the interstitial matrix, which is a crucial event involved in the majority of steps of the invasion-metastasis process.
Our group is interested in the impact of the extracellular MATRIx archiTECTURE (MATRITECTURE) on cancer cell behaviour. We have recently identified BM stiffness as a pivotal determinant of metastasis formation independent of laminin network pore size inside the BM7. Moreover, the molecular ratio between the secreted ECM protein netrin-4 and laminin determines global BM stiffness through opening ternary laminin node complexes. The degree of netrin-4 is associated with patient survival of different metastasizing solid tumor types such as breast and kidney cancer as well as melanoma. This fascinating data reveal that small non-adhesive ECM proteins might act as reversible ECM regulators, which we defined as RevMatriRegs. Our future goal is to understand single ECM protein activity on the global ECM scale and cell behaviour inside the Matritecture. We not only aim to decipher control of function of ECM proteins and their impact on cancer cell invasion but also to translate our findings into diagnostic and therapeutic applications. Our research goals will be achieved by combining biochemical, biophysical, and functional approaches together with big data modelling and mathematical simulations. Furthermore, we are interested in the communication between cancer and stromal cells and the resulted signalling programmes induced and enhanced through released ECM factors.
Key Papers:
1. Nielsen, S.R., J.E. Strobech, E.R. Horton, R. Jackstadt, A. Laitala, M.C. Bravo, G. Maltese, A.R.D. Jensen, R. Reuten, M. Rafaeva, S.A. Karim, C.I. Hwang, L. Arnes, D.A. Tuveson, O.J. Sansom, J.P. Morton, and J.T. Erler. 2021. Suppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade. Nat Commun. 12:3414.
2. Reuten, R.#, S. Zendehroud, M. Nicolau, L. Fleischhauer, A. Laitala, S. Kiderlen, D. Nikodemus, L. Wullkopf, S.R. Nielsen, S. McNeilly, C. Prein, M. Rafaeva, E.M. Schoof, B. Furtwangler, B.T. Porse, H. Kim, K.J. Won, S. Sudhop, K.W. Zornhagen, F. Suhr, E. Maniati, O.M.T. Pearce, M. Koch, L.B. Oddershede, T. Van Agtmael, C.D. Madsen, A.E. Mayorca-Guiliani, W. Bloch, R.R. Netz, H. Clausen-Schaumann, and J.T. Erler#. 2021. Basement membrane stiffness determines metastases formation. Nat Mater. 20:892-903. (featured article in June 2021 issue with News & Views; #corresponding authors).
3. Mayorca-Guiliani#, A.E., O. Willacy, C.D. Madsen, M. Rafaeva, S. Elisabeth Heumuller, F. Bock, G. Sengle, M. Koch, T. Imhof, F. Zaucke, R. Wagener, T. Sasaki, J.T. Erler#, and R. Reuten#. 2019. Decellularization and antibody staining of mouse tissues to map native extracellular matrix structures in 3D. Nat Protoc. 14:3395-3425. (#corresponding authors).
4. Krahn, N.*, M. Meier*, R. Reuten*, M. Koch, J. Stetefeld, and T.R. Patel. 2019. Solution Structure of C. elegans UNC-6: A Nematode Paralogue of the Axon Guidance Protein Netrin-1. Biophys J. 116:2121-2130. (*contributed equally first authors).
5. Reuten, R.*, T.R. Patel*, M. McDougall*, N. Rama, D. Nikodemus, B. Gibert, J.G. Delcros, C. Prein, M. Meier, S. Metzger, Z. Zhou, J. Kaltenberg, K.K. McKee, T. Bald, T. Tuting, P. Zigrino, V. Djonov, W. Bloch, H. Clausen-Schaumann, E. Poschl, P.D. Yurchenco, M. Ehrbar, P. Mehlen, J. Stetefeld, and M. Koch. 2016. Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes. Nat Commun. 7:13515. (*contributed equally first-authors).
6. Reuten, R.#, D. Nikodemus, M.B. Oliveira, T.R. Patel, B. Brachvogel, I. Breloy, J. Stetefeld, and M. Koch#. 2016. Maltose-Binding Protein (MBP), a Secretion-Enhancing Tag for Mammalian Protein Expression Systems. PLoS One. 11:e0152386. (Faculty1000 Prime recommended, #corresponding authors).
7. Grandin, M.*, M. Meier*, J.G. Delcros*, D. Nikodemus*, R. Reuten*, T.R. Patel, D. Goldschneider, G. Orriss, N. Krahn, A. Boussouar, R. Abes, Y. Dean, D. Neves, A. Bernet, S. Depil, F. Schneiders, K. Poole, R. Dante, M. Koch, P. Mehlen, and J. Stetefeld. 2016. Structural Decoding of the Netrin-1/UNC5 Interaction and its Therapeutical Implications in Cancers. Cancer Cell. 29:173-185. (*contributed equally first-authors).
References:
1 Horton, E. R. et al. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. Nat Cell Biol 17, 1577-1587, doi:10.1038/ncb3257 (2015).
2 Mayorca-Guiliani, A. E. et al. Decellularization and antibody staining of mouse tissues to map native extracellular matrix structures in 3D. Nat Protoc, doi:10.1038/s41596-019-0225-8 (2019).
3 Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559-1564, doi:10.1126/science.1203543 (2011).
4 Dillekas, H., Rogers, M. S. & Straume, O. Are 90% of deaths from cancer caused by metastases? Cancer Med 8, 5574-5576, doi:10.1002/cam4.2474 (2019).
5 Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3, 453-458, doi:10.1038/nrc1098 (2003).
6 Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275-292, doi:10.1016/j.cell.2011.09.024 (2011).
7 Reuten, R. et al. Basement membrane stiffness determines metastases formation. Nat Mater 20, 892-903, doi:10.1038/s41563-020-00894-0 (2021).