Chondrou, Panagiota;
(2022)
The role of SPARC in the pathogenesis of Squamous cell lung cancer.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Chondrou_000_Thesis.pdf - Accepted Version Download (36MB) | Preview |
Abstract
Lung cancer remains the leading cause of cancer related deaths worldwide. The tumour microenvironment of the lung plays an important role in cancer initiation and progression. The complex interplay between cancer cells and their stroma is directed by several biochemical and biophysical cues. Increased matrix stiffness is a biophysical element, which has been shown to affect several proteins associated with tumour progression. Lung cancer tissues are much stiffer than the surrounding normal tissues. Collagens are important constituents of the ECM and contribute to lung mechanics, as increased collagen levels are associated with increased tumour stiffness. Collagens are associated with other ECM proteins, such as Secreted Protein Acidic and Rich in Cysteine (SPARC). SPARC is a calcium binding matricellular glycoprotein that binds collagens in the ECM and mediates cell-matrix interaction. Published evidence, suggests SPARC is also associated with YAP/TAZ, members of the Hippo pathway and important mechanosensing proteins. YAP/TAZ sense the stiffening of the ECM and promote transcriptional activation of targeted genes. These data support the hypothesis that SPARC might be a candidate in mechanotransduction pathways. In this thesis, I examined the role of the mechanotransduction machinery and the regulation of SPARC in squamous cell lung cancer (LUSC). My data suggests that SPARC is regulated by mechanical stiffness, as it translocates to the nucleus in cells growing on rigid matrices. Furthermore, my data demonstrate that SPARC and YAP interact physically in LUSC cells in vitro and in situ. SPARC loss-of-function experiments show a role of SPARC in the regulation of YAP in LUSC cells. Decreased SPARC levels negatively affect YAP1 transcript levels and prevent YAP nuclear translocation on stiff matrices. These findings warrant further investigation to further elucidate the importance of SPARC, the mechanotransduction machinery and the Hippo pathway in the development of LUSC.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of SPARC in the pathogenesis of Squamous cell lung cancer |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10142043 |
Archive Staff Only
 |
View Item |
