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Understanding Stromal Fibroblast Heterogeneity in the Pancreatic Tumor Microenvironment

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Technical Report,01 Aug 2018,31 Jul 2019

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Oregon Health and Science University Portland United States

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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 contrary to dogma in the field, stellate cells give rise to a numerically minor subpopulation of PDAC CAFs, 2 we have generated the first transcriptional profile of PSC-derived CAFs and find that these cells express a unique gene expression program enriched in axon guidance cues, extracellular matrix components aside from collagens, and leukocyte trafficking molecules. Together, these findings pave the way for future work on our proposal to better understanding the fibroblastic compartment of the pancreatic tumor microenvironment.

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  • Medicine and Medical Research

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