The role of YAP and cell of origin during the progression of pancreatic neoplastic lesions to invasive ductal adenocarcinoma

Thesis

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most fatal cancer types with a very low survival rate. The development of dysplasia in normal ductal epithelium is the initiating step of the disease, which then undergoes multiple grades of pancreatic intraepithelial neoplasia (PanIN) lesions before developing into invasive adenocarcinoma. KRAS mutations occur during early stages of malignant transformation and act as a critical event in both initiating and maintaining PDAC development. Alongside, an oncogene, YAP, is emerging to play a role in the facilitation of neoplastic precursor lesions to invasive cancer in KRAS mutated pancreas. Canonically, YAP’s activation is negatively regulated by the tumour suppressive Hippo pathway by inhibiting the protein’s nuclear localisation. In order to elucidate the mechanism by which YAP promotes early progression of PanIN lesions, I explored the association of YAP with the components of KRAS-mediated MAPK signalling pathway. Firstly, I show an association between YAP and phosphorylated ERK1/2 both in pancreatic cancer cells and low-grade PanIN lesions of Kras-mutated mice. In these PanIN lesions, I demonstrate the nuclear expression of YAP to be heterogeneous and associate this with PanIN lesions’ origin from different cell types. I show ductal-derived precursor lesions in Kras mutated mice and PDAC in human samples to positively correlate with high nuclear expression of YAP. To further understand this role of YAP in ductal-derived PDAC, I establish YAP depleted 3D pancreatic organoid system isolated from ductal cells of Kras mutated mouse pancreas. From this study, I present the potential role of YAP as a useful marker to identify ductal-derived PanIN lesions and PDAC.

Authors: Thapa, A

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: KRAS; pancreatic cancer; YAP; Pancreatic ductal adenocarcinoma; oncogene; Genetically engineered mouse model
• Subjects: Cancer Biology