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Rajendran, R, 2023. Investigation of melanoma circulating tumour cell clusters using biomaterial surfaces. PhD, Nottingham Trent University.
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Abstract
Circulating tumour cells (CTC) disperse from primary tumours to distal anatomical sites via lymphatic and haematological vessels. This process is known as metastasis, which contributes to the majority of cancer-related mortality. Though much rarer, CTC clusters are considerably more metastatic, up to 100-fold more, than their single CTC counterpart. Around 30 – 34% of patients suffering from metastatic melanoma present CTC clusters. However, the underlying molecular mechanisms governing cluster formation and contribution to metastasis remain unknown. Using hydrophobic fluoroalkylsilica (FS) surfaces that induce multicellular aggregation-disaggregation of FM3 melanoma cells as an in vitro model, this research project discovered novel signalling molecules, such as galectin-3, 4F2hc, and MMP2, involved in homotypic aggregation-disaggregation of melanoma CTC. To promote aggregation, oligomeric galectin-3 could cross-link coterminous 4F2hc glycoproteins on adjacent cells, via the formation of glycoprotein:galectin-3:glycoprotein (GGG) bridges. At distal metastatic sites, MMP2-dependent cleavage of oligomeric galectin-3 could dissociate GGG bridges to promote disaggregation. Studies reported that β-catenin-signalling could be regulated by 4F2hc. In FM3 cells, β-catenin expression was decreased during disaggregation, highlighting the importance of β-catenin interactome in aggregation. PU.1 transcription factor is likely involved in this non-canonical β-catenin-signalling. PU.1-inhibition resulted in increased 4F2hc levels, suggesting that 4F2hc expression could be regulated by β-catenin and PU.1 in melanoma CTC. Lastly, fibronectin and vitronectin undergo denaturation caused by conformational changes associated with intermolecular β-sheets and random coils, during adsorption onto tissue culture polystyrene (TCP) surfaces but not on FS surfaces. Denaturation could expose cell-binding motifs from cryptic sites, leading to increased cellular adhesion, and multicellular disaggregation. This explains why FM3 cells readily attach to TCP surfaces but aggregate on FS surfaces. This research project demonstrates the suitability of using FS surface-based approaches to study melanoma CTC clusters. Future research could use FS surfaces to interrogate GGG bridges and CTC cluster-mediated metastasis of other cancers.
| Item Type: | Thesis |
|---|---|
| Creators: | Rajendran, R. |
| Contributors: | Name Role NTU ID ORCID |
| Date: | May 2023 |
| Rights: | The copyright in this work is held by the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the author. |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Melissa Cornwell |
| Date Added: | 04 Oct 2024 13:34 |
| Last Modified: | 04 Oct 2024 13:34 |
| URI: | https://irep.ntu.ac.uk/id/eprint/52360 |
https://orcid.org/0000-0002-7333-3549Actions (login required)
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