Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer–Associated Fibroblasts
Abstract
Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 21, 2021
- Source ID
- 10.1158/2159-8290.cd-21-0601
Entities
People
- Ariana Sattler
- Chet Oon
- Christopher C. Dufort
- David Dawson
- Duanchen Sun
- Erin J. Helms
- Hannah Sanford-Crane
- Jennifer M Finan
- M Kathrina Onate
- Mara H. Sherman
- Mark W. Berry
- R Crystal Chaw
- Rosemary Makar
- Sohinee Bhattacharyya
- Sunil R Hingorani
- Wesley Horton
- Zheng Xia
Organizations
- Fred Hutchinson Cancer Center
- National Cancer Institute
- National Institute of General Medical Sciences
- Oregon Health & Science University
- The Pew Charitable Trusts
- United States Department of Defense
- University of California, Los Angeles
- University of Washington