Epigenetic Licensing of Pancreatic Cancer Metastasis
Abstract
The vast majority of patients with pancreatic cancer adenocarcinoma (PDAC), the major form of pancreatic cancer, are diagnosed with late metastatic disease, a stage considered largely incurable due to its limited response to standard chemotherapy as well as to newer molecularly targeted and immune-based therapies. The scientific objective of this proposed project is to dissect how the initiating events of PDAC set the stage for tumor progression and metastasis, such that more effective and selective strategies for early intervention can be devised to improve patients outcomes. From a conceptual standpoint, our project builds upon our recent demonstration that a large fraction of molecular alterations associated with advanced disease stages are induced early in the neoplastic process by cooperative interactions between cancer-driving genetic mutations (mutant KRAS, found altered in ~ 95% of patients) and inflammation (pancreatitis), and that these involve large-scale changes in the packaging of DNA (epigenetic changes) that have prognostic implications in patients. This proposal will leverage these concepts and unique tools developed by the partnering PIs to study how these early molecular changes alter the identity of normal cells as they become cancerous and how the complex cellular composition of pancreatic tumors promotes disease progression, with the goal of using this information to expose more clinically effective options to prevent or treat pancreatic cancer. As cancers share many features with homeostatic processes, such as wound healing responses, our project stems from the overarching hypothesis that improving PDAC detection and interception requires a better understanding of the molecular and tissue changes that distinguish early and advanced pancreatic tumors from normal and regenerating pancreas, as well as novel experimental approaches to pinpoint those responsible for disease pathogenesis. To address this, our proposal undertakes a unique multidisciplinary approach that brings together synergistic and complementary expertise of the partnering laboratories and the broader capabilities of Dartmouth s Norris Cotton Cancer Center and the Institute for Research in Biomedicine (IRB-Barcelona) in disease modeling, functional genomics, clinical resources, and profiling platforms. Specifically, we will combine information from human specimens with innovative animal models enabling systematic interrogation of both tumor and host tissue alterations associated with disease progression to: (1) identify factors critical for sustaining malignant and metastatic competency in PDAC that are activated in early in the neoplastic process by tumor-specific epigenetic changes; (2) characterize how these early changes rewire otherwise normal inflammatory reactions to promote metastatic spread; and (3) evaluate their potential as a novel class of targets to intercept PDAC at an earlier stage. The scalability and flexibility of the in vivo model systems that will be used in this proposal, involving zebrafish and mouse models optimized by the team, will help us identify novel actionable mechanisms and biomarkers for disabling and/or detecting early PDAC progression and metastasis in an expedited manner. In the short term, we expect that this conceptually innovative research idea will uncover early, cancer-specific factors and processes through which changes in the tumor cell epigenome and co-opted host factors cooperatively drive PDAC development, and yield fundamental insights into how these early epigenetic events prime cells (and their tissue niches) for metastasis. Moreover, by defining the earliest epigenetic traits associated with cancer- and metastasis-initiating potential, we anticipate our project will pave the way for strategies to harness these to detect and disable early tumor evolution toward metastatic recurrence in PDAC. Finally, our studies will also produce new tools and in vivo methodologies of broad relev
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210813
Entities
People
- Steven Leach
Organizations
- Dartmouth College
- United States Army