Saudi Cultural Missions Theses & Dissertations
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Item Restricted The role of ASC inflammasom in Pancreatic Cancer(Saudi Digital Library, 2022-09-17) Kashgari, Bassam; Jenkines, BrendanPancreatic ductal adenocarcinoma (PDAC) is an aggressive and highly lethal malignancy. The vast majority of PDAC patients are diagnosed at an advanced and incurable stage of the disease. Even with the best current treatments, the prognosis for advanced PDAC is less than one year. While molecular targeted treatment is widely used in many malignancies with impressive results, no such “precision medicine” approach is currently used for PDAC. The dysregulation of the immune system plays a role in the progression of the disease; in fact, chronic pancreatic inflammation is a risk factor for PDAC. Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in PDAC remains ill-defined. The genetically engineered KPC mouse model mimics the molecular and cellular immunological and oncogenic processes that drive human PDAC. The genetic abolition of the Pycard gene, encoding ASC, dramatically reduced tumor growth in different age groups of KPC mice. This phenotypic reduction was associated with reduced levels of inflammasome activity and maturation for the downstream target of inflammasomes Interleukin (IL)-18 (but increased IL-1B). Subsequently, the elevated levels of IL-18, inflammation, proliferation, and apoptosis were reversed upon the genetic disruption of ASC expression in the KPC mouse model in different development stages of PDAC. Furthermore, our clinical data supports that ASC inflammasomes are over-activated and associated with poor patient survival and responsiveness to chemotherapy in PDAC. In conclusion, the findings in this work show that elevated ASC levels are a key feature of PDAC and supports the role of ASC as a tumor promoter in PDAC (e.g. tumor incidence and PDAC characteristics) through mediating IL-18 rather than IL-1B. Understanding the currently ill-defined role of ASC inflammasomes in PDAC may provide novel biomarkers and druggable candidates for targeted therapy for PDAC patients.a14 0