Dissecting the complexity of cholesterol signaling in multi-step pancreatic carcinogenesis

Pancreatic ductal adenocarcinoma (PDA) is a highly devastating disease with poor prognosis and rising incidence. Late detection, poor druggability and a particularly aggressive biology are the major challenges that determine therapeutic failure, underling the importance of research to identify markers for early detection and potential targets for the development of new and more effective therapies. Indeed, early detection can increase chance of survival and ways to detect pancreatic cancer in the earliest stages are urgently needed. Also, the identification of risk factors associated to PDA development and the characterization of their exact molecular mechanisms are crucial to improve current prevention strategies. Therefore, understanding PDA initiation is critical to enable early detection and effective prevention. Standing the key role of obesity and high-fat diet on PDA development and building on previous findings that cholesterol biosynthesis and metabolism are deregulated in premalignant acinar cells PDA tumor cells, I further interrogated the role of cholesterol in tumor initiation and progression. In my dissertation, I will extensively describe PDA and present the hallmarks that define its biology. Next, I will discuss the oncogenic role of mutant KRAS, which is universally mutated in PDA patients and drives a complex metabolic reprogramming that facilitates tumor initiation and supports tumor progression. Finally, I will provide an overview of cholesterol metabolism, trafficking and signaling nodes, unraveling a key role of cholesterol in PDA biology. The experimental work that I will present, characterizes a two-pronged role of cholesterol in acinar cells and PDA tumor cells. The first part defines the impact of exogenous administration of cholesterol on tumor initiation. I demonstrated that cholesterol supplementation facilitates acinar cells plasticity through activation of the cAMP-PKA signaling axis. The second part of the experimental work seeks to document the pro-tumorigenic activity of impaired cholesterol trafficking in PDA tumor cells. I examined the dynamics of cholesterol trafficking and prominent signaling nodes.