Project Summary:
This project focuses on investigating an important yet understudied functional genomic process, namely the role of nuclear shape, structure, and function during the initiation of pancreatic cancer. Pancreatic cancer is a devastating disease with a low five-year survival rate of 13%, and its incidence is rising rapidly, projected to become the second leading cause of cancer death in the U.S. by 2030. In Wisconsin, pancreatic cancer is the second most common cancer-related cause of death and ranks in the top quarter for pancreatic cancer mortality with an incidence rate of 13.5 and a mortality rate of 11.2 per 100,000 people. Contributing to these stark statistics, 64% of adults in Wisconsin report consuming alcohol at least once a month. This is significant because chronic alcohol use is often recognized as a contributing risk factor for pancreatic cancer. For instance, research from our laboratory and others demonstrates how pancreatitis, an inflammation of the pancreas primarily caused by alcohol consumption, can drive the initiation and progression of pancreatic adenocarcinoma (PDAC), accounting for over 90% of all tumors in the pancreas. Moreover, disparities in pancreatic cancer diagnosis and treatment, influenced by race and socioeconomic status, persist, further complicating the fight against this disease. The findings of this study have the potential to benefit all individuals affected by pancreatic cancer in Wisconsin, irrespective of their racial or socioeconomic backgrounds.
The main goal of this project is to better understand how oncogenic signaling cascades modify nuclear structure that influences gene expression networks. Mutations in KRAS and other members of its pathway (e.g., EGFR) are a universal feature of PDAC. Central to this investigation is the triple code hypothesis, which posits that genetic mutations lead to epigenetic alterations that ultimately disrupt nuclear structure. Research from this project team has provided valuable insights into this paradigm by demonstrating how KRAS-induced signaling in PDAC leads to significant disruptions in epigenetic regulators involved in nuclear reorganization. Specifically, their work has shown that KRAS signaling affects key heterochromatin remodeling factors, such as HP1 (Heterochromatin Protein 1) and EHMT (euchromatic histone methyltransferase) proteins, which are crucial for maintaining the organization of nuclear structures, including nucleolar organizer regions (NORs). By exploring how KRAS signaling reshapes nuclear architecture, one of the earliest morphological changes detected in PDAC, the researchers aim to uncover structural changes that contribute to the aggressive behavior of this malignancy. This research will deepen the understanding of the link between nuclear structure and cancer progression in PDAC, potentially informing future therapeutic approaches for this dismal disease.