Unravelling the early responses to KrasG12D activation in the adult lung epithelium

Hill, Liam 2024. Unravelling the early responses to KrasG12D activation in the adult lung epithelium. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Our lung epithelium is continuously exposed to a harsh external environment, accumulating tissue damage, infections, and harmful mutations that may have the potential to drive cancer. Activating mutations in KrasG12D are responsible for around 30% of lung cancers, with patients frequently diagnosed at later stages. At early timepoints, KrasG12D mutant cells have been shown to be eliminated from adult tissues such as the pancreas by a conserved process known as cell competition. In the lung, it is not clear if cell competition has a role in shaping the pre-neoplastic lung epithelium, or even how KrasG12D drives cancer in the distal lung epithelium. Using a well-established model of tumorigenesis in mouse lungs, cell competition was not found to regulate the lung epithelium at early timepoints post KrasG12D expression. Instead, alveolar cells that express KrasG12D undergo morphological changes that are reminiscent of transition cell state changes found in fibrotic lung disease. We identify that KrasG12D expressing alveolar type II cells undergo cellular differentiation via Krt8+ cell states, becoming less spherical and more squamous in morphology. Furthermore, pro-inflammatory recruitment of innate immune cells to the alveoli further drives differentiation of non-transformed cells ex vivo. We identify a positive correlation between the level of KrasG12D expressing cells and Krt8 expression in vivo in early adenomatous tissue. Thus, KrasG12D mutant cells in lung are subject to differentiation driven by conserved injury remodelling pathways in the alveoli. Whether or not these cell state changes are pro-tumorigenic or are an attempt to offset tumorigenesis is not yet clear, however, further elucidation of processes identified in this thesis could provide a novel marker to identify early stage disease for better detection and intervention.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	27 June 2024
Last Modified:	27 Jun 2024 13:12
URI:	https://orca.cardiff.ac.uk/id/eprint/170142

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