@article{928b8fb7bae448fc84b0badf8d0fc78f,
title = "Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation",
abstract = "Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1. In contrast, SOCS1 gene methylation and downregulation in CAF activated STAT3 and induced insulin-like growth factor-1 expression to support PDAC cell growth. Moreover, CAF facilitated methylation-dependent growth of PDAC tumor xenografts in mice. The ability of patient-derived CAF with SOCS1 methylation to promote PDAC growth was more robust than CAF without SOCS1 methylation. Overall, our results reveal how PDAC cells can reprogram CAF to modify tumor-stromal interactions in the TME, which promote malignant growth and progression.",
author = "Qian Xiao and Donger Zhou and Rucki, {Agnieszka A.} and Jamila Williams and Jiaojiao Zhou and Guanglan Mo and Adrian Murphy and Kenji Fujiwara and Jennifer Kleponis and Bulent Salman and Wolfgang, {Christopher L.} and Anders, {Robert A.} and Shu Zheng and Jaffee, {Elizabeth M.} and Lei Zheng",
note = "Funding Information: This work was conducted at the Johns Hopkins University School of Medicine. We thank Dr. Ben Park for his comments on the manuscript, Dr. Michael Goggins for his insightful discussion, and Dr. Wayne Yu at the Microarray Core for his help with microarray analyses. This work was supported in part by the NIH (R01CA169702 and K23 CA148964-01 to L. Zheng.), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (E.M. Jaffee, L. Zheng.), Lefkofsky Family Foundation (L. Zheng), the National Cancer Institute Specialized Programs of Research Excellence in Gastrointestinal CancersP50 CA062924 (E.M. Jaffee, L. Zheng), Lustgarten Foundation (L. Zheng), the Sol Goldman Pancreatic Cancer Center grants (L. Zheng). Q. Xiao is supported by the Chinese Scholarship Council Foundation 201206320056; and D. Zhou is supported by the Chinese Scholarship Council Foundation 2011632121. 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. Publisher Copyright: {\textcopyright}2016 AACR.",
year = "2016",
month = sep,
day = "15",
doi = "10.1158/0008-5472.CAN-15-3264",
language = "English (US)",
volume = "76",
pages = "5395--5404",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "18",
}