Investigating the role of Pten and Lkb1 in traditional and serrated mouse models of colorectal cancer

Derkits, Sahra (2014) Investigating the role of Pten and Lkb1 in traditional and serrated mouse models of colorectal cancer. PhD thesis, University of Glasgow.

Abstract

Colorectal cancer (CRC) is the fourth most common cancer in the UK. Despite intensive research that identified the key driver mutations, the precise consequences of each mutation and how they modify therapeutic response is unclear. More recently, it has been shown that the serrated subgroup of CRC, which is driven by oncogenic KRAS or BRAF mutations, is associated with the poorest survival.
Germline mutations in either Phosphatase and tensin homologue (PTEN) and Liver kinase B1 (LKB1) cause intestinal hamartomas that can progress to CRC. However, there is an ongoing debate whether tumourigenesis arises from the epithelial or the mesenchymal compartment of the gut and the contribution of these mutations to sporadic CRC.
The aim of this thesis was to:
• Address the role of Pten and Lkb1 in the murine intestinal epithelium
• Determine if these mutations cooperate with other driver mutations such as Apc and KRas.
• Understand the mechanistic basis that drives changes in homeostasis and tumourigenesis.
• Use recently developed small molecule inhibitors that target these aforementioned candidate pathways.
Neither Pten nor Lkb1 deficiency was sufficient to drive neoplasia in the murine intestinal epithelium. Loss of Pten in the murine epithelium does not alter intestinal homeostasis and appears to be redundant. Lkb1 deficiency causes an expansion of the goblet cells linage and activation of the Hippo pathway but only when either KRas or Apc mutations are present does this result in accelerated tumourigenesis.
Pten and KRas cause MAPK and PI3K pathway hyperactivation that results in hyperproliferation and serration of the murine gut. These precursor lesions are sensitive to MEK, PI3K/mTOR and surface Wnt inhibition. KRas driven tumours from either Lkb1 or Pten deficient mice acquire a Wnt pathway hyperactivation that drives invasion and metastasis in mice and leads to resistance of PI3K/mTOR and surface WNT inhibition.
Taken together my data has shown that KRAS mutation can initiate tumours via a serrated route which on the further deregulation of Wnt signalling convert to tumours resembling classical CRC. Importantly these tumours are now Wnt ligand independent and appear treatment resistant, analogous to the human tumours that are adenocarcinoma that bear a serrated signature. Importantly loss of either LKB1 or PTEN accelerated tumourigenesis down either the serrated or the classical route and suggests key roles for these proteins in sporadic colorectal carcinogenesis. Given the drug resistance of our models, they could be utilized as excellent therapeutic testing models that may more closely recapitulate the human disease.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Due to copyright restrictions the full text of this thesis cannot be made available online. Access to the printed version is available once any embargo periods have expired.
• Subjects: Q Science > QH Natural history > QH426 Genetics; Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
• Supervisor's Name: Sansom, Prof. Owen
• Date of Award: 2014
• Depositing User: Sahra Derkits
• Unique ID: glathesis:2014-4909
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 05 Feb 2014 15:01
• Last Modified: 03 Jan 2019 14:18
• URI: https://theses.gla.ac.uk/id/eprint/4909