Discovery and Characterisation of LNC441 in Circulating Tumour Cells

Bull, Emma C. (2025) Discovery and Characterisation of LNC441 in Circulating Tumour Cells. Doctoral thesis, University of East Anglia.

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Abstract

In a normal somatic cell, it is estimated that ~80% of the human genome is transcribed into RNA molecules but only ~2% are protein coding. Cancer cells can hijack these coding/non-coding genes and transform cells into deadly malignancies. Defining which cancer cells hijack which genes has been the backbone of contemporary precision oncology, disease subtyping, and targeted therapy development. Much of this knowledge has been generated through the analysis of donated primary tumours; however, metastasis is the leading cause of cancer related death and is thought to be an independent biological process to tumour development and therefore probably requires different sets of gene networks and cell phenotypes. Metastasis is a distinct disease component requiring specific (sub)clones to undergo complex phenotypic plasticity not required since embryogenesis; for example, detachment, invasion, migration. A significant fraction of the genome is not needed by normal cells but this ‘dark matter’ of the genome could be transcribed by metastatic cells to achieve systemic disease. Under the opportune conditions including amplifications and gene rearrangements generating novel oncogenic transcription factors, metastatic cells could engineer new RNA molecules and gene networks not observed in normal or even tumour cells. Here, we took an unbiased approach and performed single-cell RNA sequencing (scRNA-seq) in metastatic osteosarcoma and Ewing sarcoma patient derived circulating tumour cells (CTCs) and discovered a completely new cohort of unannotated RNAs. This work contains characterisation of a candidate long non-coding RNA that was significantly overexpressed in CTCs. This characterisation comprises in silico and in vitro modelling. Experimental work to determine the clinical significance of these RNAs is ongoing, using gain- and loss-of-function mutants and orthotopic xenograft mouse models.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Chris White
Date Deposited:	03 Dec 2025 10:46
Last Modified:	03 Dec 2025 10:46
URI:	https://ueaeprints.uea.ac.uk/id/eprint/101217
DOI:

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