Absence of Enhancer of Zeste Homolog 2 Promotes the Progression of KRAS-Driven Pancreatic Ductal Adenocarcinoma
Master of Science
Physiology and Pharmacology
Dr. Christopher Pin
Pancreatic ductal adenocarcinoma (PDAC) is estimated to be the second deadliest cancer by 2030. Previous studies showed constitutive activation of KRAS (KRASG12D) is a key genetic driver of PDAC, accelerated by deletion of the epigenetic regulator Enhancer of Zeste Homologue 2 (EZH2). However, contradictory findings suggest multiple roles for EZH2. The goal of this study was to define EZH2’s contributes to early KRASG12D-driven PDAC. I hypothesized that EZH2 restricts KRASG12D initiation of PDAC in response to injury. To address this hypothesis, genetically modified mice with targeted deletion of the SET domain of Ezh2 +/- KRASG12D were exposed to cerulein-induced pancreatic injury and examined for pancreatic lesions. Histological analysis for markers of tissue damage and inflammation showed loss of EZH2 caused no difference in the pre-neoplastic lesion formation but did affect progression, and reduced immune cell infiltration, suggesting a role for EZH2 in limiting early progression of KRASG12D-mediated PDAC.
Summary for Lay Audience
In this study, I examined the role of an enzyme Enhancer of Zeste Homologue 2 (EZH2) in the most common type of pancreatic cancer called pancreatic ductal carcinoma (PDAC) in the presence of KRAS mutation in mice. The majority of PDAC patients bear KRAS mutations in their genome. Our previous work showed that there are no differences in the severity of pancreatic tissue injury whether you delete EZH2 or not. However, other studies indicate that EZH2 deletion make the effects of KRAS mutation much stronger on the development of PDAC. Therefore, I wanted to know if the loss of EZH2 beneficial or harmful for pancreatic tissue recovery from injury in the context of KRAS mutation. My work showed that the loss of EZH2 results in more progressive pancreatic lesions, which increase the possibility of developing into cancer. In addition, I observed more immune cells appeared around the pancreatic lesions of mice lacking Ezh2 expression. My results suggest that EZH2 plays an important role in the development of pancreatic cancer and may be a potential target for anti-cancer therapy.
Wang, Xiaoyi, "Absence of Enhancer of Zeste Homolog 2 Promotes the Progression of KRAS-Driven Pancreatic Ductal Adenocarcinoma" (2022). Electronic Thesis and Dissertation Repository. 8900.