Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.789481
Title: Targeting the actin polymerisation pathway for improved treatment of glioblastoma
Author: Ketchen, Sophie Elizabeth
ISNI:       0000 0004 8501 0784
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
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Abstract:
One of the most devastating hallmarks of cancer is invasion, a prerequisite for tumour metastasis. Recently, the concept of migrastatics, a term used for drugs that interfere with cancer cell invasion/migration, has championed the development of drugs targeting the actin polymerisation pathway, as a main driver of cell migration. Targeting this cellular phenomenon offers an opportunity to improve the treatment of invasive and highly migratory tumours such as glioblastoma (GBM) and to better understand the mechanisms controlling glioma cell migration. In this study, a small molecule inhibitor, CCG-1423, was identified that distinctively failed to halt migration. These observations suggest that cells continue to migrate via mesenchymal-amoeboid transition (MAT). Immunofluorescence studies and western blotting supported this novel MAT switch by demonstrating the loss of nuclear MKL1, a regulator of CCN1; a key adhesion and secretory protein in mesenchymal cell migration. MAT induction was confirmed at high resolution by Instant Structured Illumination Microscopy (iSIM) and a newly developed ImageJ plugin allowing identification and quantification of MAT associated features such as lamellipodia or filopodia. This approach allowed for the first time, the detailed characterisation of CCG-1423 effects on MAT in gliomas. Clinical relevance of CCN1 was established by an association with tumour grade including increases in CCN1 concentration detected in matched patient blood samples. CCN1 levels were significantly increased in recurrent patient blood samples in comparison to their primary blood samples, suggesting that CCN1 is a key player in GBM invasion and progression. The presented findings support pharmacological intervention with migrastatics through the development of combination treatments to target both mesenchymal and amoeboid cell migration in GBM management to fully inhibit invasion. In addition, this work has generated compelling evidence that CCN1 is a potential blood biomarker to monitor and potentially predict GBM recurrence earlier, therefore increasing survival rates of this devastating disease.
Supervisor: Brüning-Richardson, Anke ; Ladbury, John E. ; Short, Susan C. Sponsor: PPR Foundation ; Musella Foundation ; North American Foundation for the University of Leeds
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.789481  DOI: Not available
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