Machado de Morais Ferreira, R; (2015) Investigating the origins of Pancreatic Ductal Adenocarcinoma. Doctoral thesis , UCL (University College London).

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) comprises 85% of all pancreatic cancers and is characterised by an extremely poor prognosis. It is becoming increasingly obvious that attention has to be focused on early tumour development, when the disease is still manageable. Thus, in this study, I aimed to assess the contribution of adult acinar and duct cells to PDAC development and to identify PDAC tumour-initiating cells (TICs). Our laboratory had previously identified Fbw7 as a potent tumour suppressor in PDAC (unpublished data). Fbw7F/F; KRasLSL-G12D/wt; Pdx1-Cre mice exhibited accelerated PDAC onset compared with KRasLSL-G12D/wt; Pdx1-Cre mice. I confirmed this observation and demonstrated that Fbw7 loss in the pancreatic epithelium had a greater proliferative effect in ductal cells, in the presence and absence of KRasG12D, leading to increased numbers of duct cells positive for phosphorylated histone 3. The selective loss of Fbw7 in adult ductal cells with concomitant KRasG12D expression (Fbw7F/F; KRasLSLG12D/ wt; Ck19-CreER mice) led to PDAC development, which was not preceded by mucinous lesions. These results were confirmed with the loss of p53 with simultaneous KRasG12D expression in adults duct cells (p53F/F; KRasLSL-G12D/wt; Ck19-CreER mice). The absence of mucinous PDAC precursors was not dependent on the genotype, as loss of Fbw7 in KRasG12D-expressing acinar cells allowed the development of mucinous murine pancreatic intraepithelial neoplasia (PanIN). Additionally, I induced bystander PanINs using orthotopic transplantation of PDAC cells. These results provide evidence that ductal cells can originate PDAC and that different pancreatic cells types might adopt different routes to PDAC development. Additionally, the observation of bystander PanINs questioned the sole pre-neoplastic nature of these lesions highlighting the need for a deeper understanding of PDAC biology. In the present work, I have also described a new marker of TICs within PDAC derived from pancreatic progenitors and adult ductal cells. Marker-high PDAC cells exhibited higher in vitro organoid-forming capacity, compared with marker-low cells, isolated from the primary tumour and after long-term cultures. Contrasting with marker-low tumour cells, marker-high cells were capable of forming secondary tumours at low numbers, demonstrating efficient tumour-initiating capacity and recapitulating the histology of the primary tumour source. These results could provide useful information for the development of PDAC targeted therapies

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