Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.783860
Title: Targeting nuclear size for therapeutic intervention in cancer
Author: Rizzotto, Andrea
ISNI:       0000 0004 7969 4403
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Abstract:
Nuclear size normally scales with cell size and is maintained throughout the cell cycle, but in cancer this karyoplasmic ratio, the ratio between the cytoplasm and the nucleoplasm, is disrupted, particularly in certain types of more metastatic tumours from certain cancer types. As the direction and scale of nuclear size changes differs for particular tumour types - for example in breast cancer larger nuclear size correlates with increased metastasis while for lung cancer smaller nuclear size correlates with increased metastasis - there must be tissue-specific drivers of these changes. This study aimed to screen several tissue-specific nuclear envelope transmembrane proteins (NETs) and separately a small molecule compound library for effects on nuclear size in cell lines from different cancer types. The NET screen was engaged in cells from prostate cancer (PC3) and cervical carcinoma (HeLa) and different sets of NETs affected nuclear size in each tumour type. Interestingly, these NETs also exhibited altered gene copy numbers in patient samples from particular tissue cancer types where their effects on nuclear size correlated with the directionality of nuclear size changes in the tumours. The compound screen was performed on the PC3 cells and on colonic adenocarcinoma (HCT116) and small cell lung carcinoma (H1299) cells. Each cancer type screened was affected by different compounds, so that both screens suggest a tissue-specific regulation of nuclear size. Interestingly, these compounds also reduced cell migration in wound healing assays, suggesting they might reduce tumour metastatic spread. Finally, merging both screens, the NET DHRS7/NET50 and the compound estradiol proprionate that both affect nuclear size in the prostate cancer model seem to intersect in the same pathway and we anticipate that further study will elucidate a mechanism for the nuclear size defects in late-stage prostate cancer.
Supervisor: Schirmer, Eric ; Arulanandam, Jeyaprakash Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.783860  DOI: Not available
Keywords: Nuclear Envelope Transmembrane proteins ; NETs ; nuclear size changes ; karyoplasmic ratio ; nuclear size defects
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