THE DUAL ROLE OF BETA-CATENIN SIGNALING IN PANCREATIC INFLAMMATION AND TUMORIGENESIS: WHEN ENOUGH IS ENOUGH

Acute pancreatitis (AP), a sudden and severe pancreatic inflammation, is a common and potentially life-threatening ailment. Recurring episodes or unresolved injury can lead to chronic pancreatitis (CP), a entrenched risk factor in developing pancreatic cancer, including both Pancreatic Neuroendocrine Tumors (PNETs) and the more prevalent Pancreatic Ductal Adenocarcinoma (PDAC). The transition from inflammation to neoplasia involves complex molecular changes, notably the dysregulation of cellular signaling pathways that govern tissue repair, immune responses, and cell proliferation. Despite advancements in supportive care, both inflammatory and neoplastic pancreatic diseases remain associated with substantial morbidity and mortality, emphasizing the critical necessity for innovative therapeutic approaches that address the essential molecular pathways propelling disease advancement. Among the key molecular regulators implicated in both pancreatic inflammation and tumorigenesis, β-catenin stands out as a central player. Atypical activation of β-catenin signaling has been associated with heightened inflammatory responses, tissue remodeling, and the initiation and progression of pancreatic tumors. Nevertheless, the precise roles of β-catenin in mediating the transition from pancreatic inflammation to cancer, the full extent of its implications as a therapeutic target remains to be comprehensively elucidated.

This dissertation explores the role of β-catenin signaling in both inflammatory and neoplastic pancreatic diseases. The first project investigates the therapeutic potential of Zyflamend, a polyherbal formulation, in modulating β-catenin activity and mitigating acute pancreatitis. The second project examines the functional relationship between β-catenin and pyruvate kinase M2 in pancreatic neuroendocrine tumor cells, elucidating how this axis governs tumor cell survival, proliferation, and resistance to chemotherapy. Findings from both projects identify a dual role for β-catenin in modulating pancreatic homeostasis, suggesting its critical involvement in maintaining healthy pancreatic function and its dysregulation in disease. This understanding has significant clinical relevance, as it opens doors for developing targeted therapies that restore β-catenin's homeostatic balance to prevent or treat pancreatic inflammation and cancer.