@article{478f50becfea4a4699508fb5ee8215a2,
title = "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 SIGNIFICANCE: By tracking and ablating a specific CAF population, we fin d tha t a numericall y minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor micro-environment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs.",
author = "Helms, {Erin J.} and Berry, {Mark W.} and Chaw, {R. Crystal} and Dufort, {Christopher C.} and Duanchen Sun and Onate, {M. Kathrina} and Chet Oon and Sohinee Bhattacharyya and Hannah Sanford-Crane and Wesley Horton and Finan, {Jennifer M.} and Ariana Sattler and Rosemary Makar and Dawson, {David W.} and Zheng Xia and Hingorani, {Sunil R.} and Sherman, {Mara H.}",
note = "Funding Information: We thank all members of the Sherman lab, Jae Myoung Suh, and Sara Courtneidge for helpful conceptual input on this work and Markus Grompe, Hiroyuki Nakai, Shin-Heng Chiou, and Monte Winslow for guidance on the intraductal AAV delivery approach. This work was supported by the OHSU Molecular Virology Core, Knight BioLibrary (and particularly by operations supervisor Danielle Galipeau and by Christopher Corless in his capacity as chief medical officer of the Knight Diagnostic Laboratories), Flow Cytometry Shared Resource, Massively Parallel Sequencing Shared Resource, Advanced Light Microscopy Shared Resource, and Histopathology Shared Resource, with core facility support from the Knight Cancer Institute Cancer Center Support Grant P30 CA069533. Funding to support this study came from NIH grant T32 GM071338 (to E.J. Helms), NIH grants R01 CA161112 and U01 CA224193 (to S.R. Hingorani), and NIH grant R01 CA250917; DOD Peer Reviewed Cancer Research Program grant W81XWH-18?1-0437 (to M.H. Sherman); and a Pew-Stewart Scholar Award (to M.H. Sherman). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Funding Information: We thank all members of the Sherman lab, Jae Myoung Suh, and Sara Courtneidge for helpful conceptual input on this work and Markus Grompe, Hiroyuki Nakai, Shin-Heng Chiou, and Monte Winslow for guidance on the intraductal AAV delivery approach. This work was supported by the OHSU Molecular Virology Core, Knight BioLibrary (and particularly by operations supervisor Danielle Galipeau and by Christopher Corless in his capacity as chief medical officer of the Knight Diagnostic Laboratories), Flow Cytometry Shared Resource, Massively Parallel Sequencing Shared Resource, Advanced Light Microscopy Shared Resource, and Histopathology Shared Resource, with core facility support from the Knight Cancer Institute Cancer Center Support Grant P30 CA069533. Funding to support this study came from NIH grant T32 GM071338 (to E.J. Helms), NIH grants R01 CA161112 and U01 CA224193 (to S.R. Hingorani), and NIH grant R01 CA250917; DOD Peer Reviewed Cancer Research Program grant W81XWH-18–1-0437 (to M.H. Sherman); and a Pew-Stewart Scholar Award (to M.H. Sherman). Publisher Copyright: {\textcopyright} 2021 The Authors; Published by the American Association for Cancer Research.",
year = "2022",
month = feb,
day = "1",
doi = "10.1158/2159-8290.CD-21-0601",
language = "English (US)",
volume = "12",
pages = "484--501",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "2",
}