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Investigating translation dysregulation in epithelial-mesenchymal transition (EMT) in human primary lung adenocarcinoma

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thesis
posted on 14.01.2022, 12:41 by Samantha Sinnadurai
In solid tumours, metastasis is the immediate cause of most cancer-related death and is orchestrated by epithelial-to-mesenchymal transition (EMT) of tumour cells. EMT manifests as the dedifferentiation of epithelial cells into mesenchymal cells, and is typified by loss of E-cadherin and cytokeratin and gain of TWIST, N-cadherin and vimentin expression. While EMT is well-characterised in in vitro models, classical morphological EMT evidence (i.e. morphological dedifferentiation/sarcomatoid change) is rare in primary tumours. mRNA translation is a highly regulated process which has been linked to EMT in cell-based studies but not in primary tumours. This project aims to investigate whether I can find evidence of EMT and of translational dysregulation in EMT in primary lung adenocarcinoma. To answer these questions, we applied histological techniques such as immunohistochemistry and in situ hybridisation methods to quantify markers of EMT and translational control and perform statistical analysis to 942 human primary lung adenocarcinoma cases to evaluate association of EMT with tumour growth pattern, physio-pathological factors and translation dysregulation. I have shown that partial EMT state is detected in all tumour growth patterns but there is an association between partial EMT and primary solid lung adenocarcinoma. EMT can be variable within whole tumour section. EMT markers are strongly associated with physio-pathological measures of invasiveness namely lymph nodes metastasis. Furthermore, there are significant associations between EMT markers and some translation factors, particularly with the phosphorylation of eukaryotic initiation factor (eIF) 4E and the α subunit of eIF2. These data suggest that partial EMT is related to solid tumour growth pattern, and that alterations in the translation initiation machinery may play a role in activating invasive and metastatic program simultaneously in human primary lung adenocarcinoma.

History

Supervisor(s)

John Le Quesne; Catrin Pritchard

Date of award

27/09/2021

Author affiliation

Leicester Cancer Research Centre

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en