p53 and the role of autophagy in pancreatic cancer development

Rosenfeldt, Mathias Tillmann (2013) p53 and the role of autophagy in pancreatic cancer development. PhD thesis, University of Glasgow.

Abstract

Autophagy is an intracellular catabolic process that involves the sequestration of proteins and whole organelles into specialized cargo vesicles (autophagosomes) and their delivery to lysosomes with subsequent degradation. Autophagy is active at low levels at any time in virtually all cells and can be induced upon a variety of different stimuli. The core function of autophagy is the degradation and recycling of intracellular material. However, how this impacts on cellular survival likely depends on the biological context.
The role of autophagy in cancer is very complex and incompletely understood. It is therefore very surprising that few studies exists that employ genetically modified mouse models of human cancer to examine the role of autophagy in this context. This is even more true when considering, that pharmacological inhibition of autophagy is currently being used in several clinical trials to treat cancer of various origins. The goal of this study was to examine the role of autophagy in a mouse model of pancreatic cancer. To achieve this several mouse strains were crossed: a) Pdx1-Cre LSLKRasG12D/wt mice that develop Pancreatic Ductal Adenocarcinoma (PDAC) similar to humans initiated by oncogenic Ras and b) Atg5flox/flox or Atg7flox/flox mice that permit Cre-induced deletion of either one of the essential autophagy regulating genes 5 and 7 (Atg5, Atg7). Offspring allowed us to examine the role of autophagy in pancreatic function.
Loss of autophagy in the pancreas leads to exocrine and endocrine tissue destruction and reduces survival in approx. 60% of animals. The early death in autophagy-deficient mice can be delayed by additional deletion of p53; the mortality rate however remains unchanged. Moribund mice show a diabetic phenotype with elevated blood glucose and fructosamine levels. In the absence of oncogenic Ras autophagy deletion does not lead to cancer formation or occurrence of pre-malignant lesions in mice aged up to 700d.
In mice that express oncogenic Ras in the pancreas (Pdx1-CreKRasG12D/wt) additional, genetic deletion of autophagy leads to accumulation of pre-malignant Pancreatic Intraepithelial Neoplasias (PanINs) that unlike their autophagy proficient counterparts never progress to cancer. In this genetic context autophagy therefore serves as a tumour promotor. In stark contrast in mice expressing oncogenic Ras and lacking both copies of p53 (Pdx1-KRasG12D/wt p53-/-) inhibition of autophagy, either genetically by deletion of Atg5, Atg7 or pharmacologically by chloroquine, tumour onset is accelerated. Therefore in a p53-deficient situation autophagy is now a tumour suppressor. Tumours that developed from a p53-proficient background have increased autophagy compared to tumours that developed from a p53-null background. Furthermore p53-/- Atg7-/- tumours have increased glycolysis in vitro and in vivo and enhanced intracellular metabolites of the anabolic Pentose Phosphate Pathway (PPP) compared to p53-/- Atg7+/+ tumours.
In summary it is the p53 status that determines the role of autophagy in PDAC development. In tumours developing from a p53-proficient background loss of autophagy completely prevents cancer development; whereas in tumours arising from p53-deficient tissue loss of autophagy accelerates tumour formation.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: autophagy, pancreatic cancer, cancer
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
• Supervisor's Name: Ryan, Prof. Kevin M.
• Date of Award: 2013
• Depositing User: MD, PhD Mathias T Rosenfeldt
• Unique ID: glathesis:2013-4961
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 21 Feb 2014 09:47
• Last Modified: 10 Mar 2017 11:36
• URI: https://theses.gla.ac.uk/id/eprint/4961