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. Cancer Res; 76(18); 5395-404. ©2016 AACR.
authors: The Second Affiliated Hospital of the Zhejiang University School of Medicine, Hangzhou, China. Zhejiang University School of Medicine, Hangzhou, China. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Qian
authors: Q
authors: Xiao
authors: The Second Affiliated Hospital of the Zhejiang University School of Medicine, Hangzhou, China. Zhejiang University School of Medicine, Hangzhou, China. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Donger
authors: D
authors: Zhou
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Agnieszka A
authors: AA
authors: Rucki
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Jamila
authors: J
authors: Williams
authors: The Second Affiliated Hospital of the Zhejiang University School of Medicine, Hangzhou, China. Zhejiang University School of Medicine, Hangzhou, China. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Jiaojiao
authors: J
authors: Zhou
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Guanglan
authors: G
authors: Mo
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Adrian
authors: A
authors: Murphy
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Kenji
authors: K
authors: Fujiwara
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Jennifer
authors: J
authors: Kleponis
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Bulent
authors: B
authors: Salman
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Christopher L
authors: CL
authors: Wolfgang
authors: The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Robert A
authors: RA
authors: Anders
authors: Zhejiang University School of Medicine, Hangzhou, China.
authors: Shu
authors: S
authors: Zheng
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Elizabeth M
authors: EM
authors: Jaffee
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland. The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. lzheng6@jhmi.edu.
authors: Lei
authors: L
authors: Zheng
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics*; D059016:Tumor Microenvironment
chemical_list: D000071222:Suppressor of Cytokine Signaling 1 Protein