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Heterotypic cell-cell interactions between KrasG12D cells and normal neighbours in early pancreatic cancer

Hill, William 2018. Heterotypic cell-cell interactions between KrasG12D cells and normal neighbours in early pancreatic cancer. PhD Thesis, Cardiff University.
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Abstract

At the initial stages of tumourigenesis, transformation occurs in a single cell within a healthy epithelial sheet. Competitive interactions between normal and Ras-transformed cells can drive the elimination of mutant cells from tissues to protect from carcinogenesis. Moreover, we have previously demonstrated that normal cells detect and eliminate Ras-transformed cells via differential EphA2 signalling. KrasG12D expressing cells (KrasG12D cells) initiate and drive the earliest stages of pancreatic cancer yet it is unclear if normal pancreatic cells can eliminate oncogenic cells. Here we use low level, stochastic induction of KrasG12D mutations in the pancreas to model the interaction of normal and transformed epithelial cells. We show that Ras-transformed cells adopt a contractile morphology and are eliminated from healthy tissue when present at low numbers. When surrounded by normal cells, KrasG12D cells become segregated, increase in compactness and are often extruded. We find that E-cadherin-based cell-cell contacts are downregulated and internalised in mutant cells when surrounded by normal neighbours in an EphA2-dependent manner. Our evidence also suggests that normal cells suppress progression of Ras-transformed cells to an early disease state. Together, this study suggests that non-transformed pancreatic epithelial cells can eliminate KrasG12D cells from the tissue via EphA2 signalling. These data identify a novel putative tumour-suppressive mechanism in the adult pancreas that mutant cells must first overcome to drive tumourigenesis. Understanding the earliest stages of pancreatic carcinogenesis will provide insight into how risk factors promote disease and may elucidate how pancreatic cancer spreads around the body.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Uncontrolled Keywords: Cell competition, pancreatic cancer
Funders: Medical Research Council
Date of First Compliant Deposit: 30 January 2019
Date of Acceptance: 30 January 2019
Last Modified: 01 Feb 2019 11:22
URI: http://orca-mwe.cf.ac.uk/id/eprint/119038

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