Understanding Stromal Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment
Abstract
Objective and Rationale: In 2016, pancreatic cancer overtook breast cancer to become the third leading cause of cancer-related death in the United States. Therapies used to treat pancreatic cancer to date have provided limited benefit, suggesting that an improved understanding of complex mechanisms of disease progression is needed to develop effective therapeutic strategies. Pancreatic cancer is characterized in part by an exuberant fibrotic and inflammatory reaction that infiltrates and surrounds the tumor, together known as the tumor microenvironment. This tumor microenvironment is thought to contribute to the broad resistance of pancreatic tumors to therapeutic intervention, including conventional chemotherapy and immune-targeted therapy. The non-cancerous cell types that foster the tumor microenvironment in pancreatic cancer, known as fibroblasts, are poorly understood. Evidence suggests that these cells support tumor progression by providing pro-growth signals, suppressing immune attack of cancer cells, and creating a physically stiff environment that cannot be efficiently penetrated by chemotherapy-carrying blood vessels. However, recent work has highlighted the complexity of the fibroblast population in pancreatic cancer, suggesting that multiple subpopulations exist and that these cells may function both to support and to suppress pancreatic cancer progression. The work proposed here will use genetic tools, mouse modeling, and molecular analyses to characterize the origins and functions of distinct fibroblast populations in the microenvironment of pancreatic cancer. These results may point to new ways to stratify patients or to novel stromal pathways to be targeted for therapeutic benefit. Principal Investigator: The Principal Investigator, Dr. Mara Sherman, is a new Assistant Professor at Oregon Health & Science University (OHSU). She did her graduate work at the University of California, Los Angeles (UCLA), where she gained a strong foundation in molecular biology, cancer biology, and use of mouse models. As a postdoctoral fellow at the Salk Institute, she initiated a pancreatic cancer research program in the lab of her mentor, Dr. Ronald Evans, to investigate how nuclear hormone receptors and their ligands regulate the pancreatic tumor microenvironment. This work launched her career in pancreatic cancer biology, with a strong focus on transcriptional regulation of the tumor microenvironment. Dr. Sherman is committed to a career in pancreatic cancer research and is well-positioned to become a leader in this growing field, with support from fellow pancreatic cancer scientists and from clinicians at OHSU. The Brenden-Colson Center for Pancreatic Care at OHSU provides a centralized means for collaboration and interaction with basic researchers and physicians with an interest in pancreatic cancer, providing an invaluable source of patient samples, research resources for pancreatic cancer modeling, and insight from scientists in her field. This network will help Dr. Sherman advance her studies of the pancreatic tumor microenvironment, and the clinical connections will enable any relevant findings in her lab to be translated to the clinic to help patients as quickly as possible. She will be further supported by her Designated Mentor, Dr. Sara Courtneidge, who has advised more than 30 scientists in her own laboratory who have each gone on to further training and/or independent positions. In addition to mentoring within her own lab, she also serves on several junior faculty mentoring committees, and she mentored junior faculty at her previous institution. She has served on numerous advisory boards and grant review committees and has made critical contributions to our understanding of oncogenic signal transduction. Impact: These studies have the potential to make an impact on pancreatic cancer research by laying the foundation for development of microenvironment-targeted therapies. Therapies based o
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810437
Entities
People
- Mara Sherman
Organizations
- Oregon Health & Science University
- United States Army