Understanding Stromal Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment
Abstract
Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in pancreatic ductal adenocarcinoma (PDAC), and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, and other fibroblast sources are likely. During the funding period, we have analyzed our novel mouse model which allows us to study PSC differentiation and function during pancreatic tumor progression in vivo for the first time. Our two most significant findings from the funding period are 1) using a marker combination identified from RNA-seq data generated during year 1 of funding, we identified PSC-derived CAFs in human PDAC at a frequency similar to that seen in mice, 2) we have generated several p53 mutant versus loss-of-function systems and identified a critical role for tumor cell-intrinsic p53 status in regulation of stromal evolution. Together, these findings pave the way for future work on our proposal to better understanding the fibroblastic compartment of the pancreatic tumor microenvironment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2021
- Accession Number
- AD1201581
Entities
People
- Mara Sherman
Organizations
- Oregon Health & Science University