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Exploration of circadian dysregulation in cancer
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Usselmann, Laura (2021) Exploration of circadian dysregulation in cancer. PhD thesis, University of Warwick.
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WRAP_Theses_Usselmann_2021.pdf - Submitted Version - Requires a PDF viewer. Download (56Mb) | Preview |
Official URL: http://webcat.warwick.ac.uk/record=b3763679~S15
Abstract
The relationship between the circadian molecular clock and cancer is complex and incompletely understood. This thesis attempts to elucidate the circadian behaviour of in vitro , in ovo, and in vivo model systems using a combination of approaches, in order to inform our understanding of the circadian clock in malignancy.
Bioluminescent reporters, qPCR and next generation sequencing methods were employed to demonstrate significant disruption to circadian clock gene activity in MCF10A cells, a non-malignant cell line frequently described by the literature as having healthy clock function. Meanwhile the malignant MCF7 cell line also demonstrated significant circadian clock gene disruption under a multitude of synchronisation/entrainment conditions. These findings highlight the challenges of using 2D in vitro models to elucidate circadian behaviour in cancer.
The chick chorioallantoic membrane (CAM) assay was adapted in order to translate 2D circadian cancer models to a 3D environment. The intrinsic molecular clock of the chicken embryo appeared not to be free-running at EDD12-14. The detection of bioluminescent reporters in ovo, a relatively new development to the CAM assay, proved challenging for reasons that remain unclear.
The machine learning biological time prediction algorithm TimeTeller, was adapted for use with low-resolution multi-tissue RNA-seq data, to predict biological time and clock dysfunction from single biological samples. The trained TimeTeller model was validated on several independent publicly available datasets. It is hoped that the application of TimeTeller to single biological samples will prove useful in understanding the degree of clock function in tumours and surrounding tissues.
Overall these findings progress our understanding of the state of the molecular circadian oscillator across a range of model systems. It is hoped that the application of this research will enable novel insights into the circadian clock in malignancy.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
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Library of Congress Subject Headings (LCSH): | Circadian rhythms, Cancer -- Research, Cancer -- Treatment | ||||
Official Date: | July 2021 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Dallmann, Robert ; Ott, Sascha | ||||
Sponsors: | Medical Research Council (Great Britain) | ||||
Extent: | 277 leaves : illustrations (colour), charts | ||||
Language: | eng |
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