Abstract
Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis.
Highlights
Pancreatic cancer is the third leading cause of cancer-related deaths in the UnitedStates
To dissect the molecular mechanisms of enhancer activation/inactivation during pancreatic ductal adenocarcinoma (PDA) metastasis, we developed 3D organoid culture using PDA cells collected from the primary tumors and matched metastatic lesions derived from the Kras+/LSL-G12D ; Trp53+/LSL-R172H ; Pdx1-Cre (KPC) PDA mouse model [36]
The inability to identify a recurrent genetic mutation driving PDA metastasis suggests that epigenetic alterations are especially important for the tumor-to-metastasis transition and that targeting epigenetic regulators may be an effective strategy for treating late-stage patients
Summary
Pancreatic cancer is the third leading cause of cancer-related deaths in the United. States. Epiof 14 genetic mechanisms regulate gene transcription, and the proper functioning of these mechanisms is essential for normal development and tissue differentiation. When these mechanisms are aberrantly altered in cancer cells, they can silence tumor suppressor are aberrantly altered in cancer cells, they can silence tumor suppressor genes or promote genes or promote the expression of oncogenes to confer advantageous adaptations of the the expression of oncogenes to confer advantageous adaptations of the cancer cells, such as cancer cells, such as increased survival and proliferation, leading to aggressive cell pheincreased survival and proliferation, leading to aggressive cell phenotypes and metastasis
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