Micalet, Auxtine;
Tappouni, Luke J;
Peszko, Katarzyna;
Karagianni, Despoina;
Lam, Ashley;
Counsell, John R;
Quezada, Sergio A;
... Cheema, Umber; + view all
(2023)
Urokinase-type plasminogen activator (uPA) regulates invasion and matrix remodelling in colorectal cancer.
Matrix Biology Plus
, 19-20
, Article 100137. 10.1016/j.mbplus.2023.100137.
Preview |
PDF
1-s2.0-S2590028523000108-main.pdf - Published Version Download (7MB) | Preview |
Abstract
Background Cancer cells remodel their local physical environment through processes of matrix reorganisation, deposition, stiffening and degradation. Urokinase-type plasminogen activator (uPA), which is encoded by the PLAU gene, is an extracellular proteolytic enzyme known to be involved in cancer progression and tumour microenvironment (TME) remodelling. Perturbing uPA therefore has a strong potential as a mechano-based cancer therapy. This work is a bioengineering investigation to validate whether 1) uPA is involved in matrix degradation and 2) preventing matrix degradation by targeting uPA can reduce cancer cell invasion and metastasis. Methods To this aim, we used an engineered 3D in vitro model, termed the tumouroid, that appropriately mimics the tumour’s native biophysical environment (3 kPa). A CRISPR-Cas9 mediated uPA knockout was performed to introduce a loss of function mutation in the gene coding sequence. Subsequently, to validate the translational potential of blocking uPA action, we tested a pharmacological inhibitor, UK-371,801. The changes in matrix stiffness were measured by atomic force microscopy (AFM). Invasion was quantified using images of the tumouroid, obtained after 21 days of culture. Results We showed that uPA is highly expressed in invasive breast and colorectal cancers, and these invasive cancer cells locally degrade their TME. PLAU (uPA) gene knock-out (KO) completely stopped matrix remodelling and significantly reduced cancer invasion. Many invasive cancer gene markers were also downregulated in the PLAU KO tumouroids. Pharmacological inhibition of uPA showed similarly promising results, where matrix degradation was reduced and so was the cancer invasion. Conclusion This work supports the role of uPA in matrix degradation. It demonstrates that the invasion of cancer cells was significantly reduced when enzymatic breakdown of the TME matrix was prevented. Collectively, this provides strong evidence of the effectiveness of targeting uPA as a mechano-based cancer therapy.
| Type: | Article |
|---|---|
| Title: | Urokinase-type plasminogen activator (uPA) regulates invasion and matrix remodelling in colorectal cancer |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.mbplus.2023.100137 |
| Publisher version: | https://doi.org/10.1016/j.mbplus.2023.100137 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | 3D models, Tumour microenvironment, CRISPR-Cas9, Urokinase-type plasminogen activator, uPA, Cancer invasion, Mechano-based cancer therapy, Stiffness |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10182461 |
Archive Staff Only
 |
View Item |
