UC Davis

Pancreatic ductal adenocarcinoma (PDA) presents a significant challenge in oncology due to its aggressive nature and limited treatment options. Despite advancements in understanding the genomic landscape of PDA initiation and progression, the mechanisms driving metastasis remain elusive. This doctoral thesis explores the critical role of epigenetic mechanisms, specifically focusing on transcriptional regulation, histone modification, and molecular crowding in PDA metastasis. Through a multidisciplinary approach, encompassing genomic analyses, functional studies, and biophysical investigations, the thesis sheds light on the intricate interplay between genetic and epigenetic factors driving PDA progression. Chapters elucidate the aberrant expression of the homeodomain transcription factor EN1 in PDA, its impact on downstream signaling pathways, and its promotion of PDA transformation and metastasis. Furthermore, the thesis uncovers the influence of nucleoplasmic macromolecular crowding, particularly highlighting the role of nesprin-3, in regulating nuclear dynamics and metastatic potential in PDA. By integrating genetic, epigenetic, and biophysical perspectives, this work not only advances our understanding of PDA pathogenesis but also paves the way for the development of targeted therapeutic interventions. Additionally, the thesis underscores the significance of pancreatic cancer organoid models in recapitulating disease progression, elucidating molecular dynamics, and guiding precision medicine approaches. Overall, this research underscores the importance of a comprehensive approach in deciphering the complexities of PDA and offers valuable insights for future therapeutic strategies aimed at improving patient outcomes.