Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation

Qian Xiao, Donger Zhou, Agnieszka A. Rucki, Jamila Williams, Jiaojiao Zhou, Guanglan Mo, Adrian Murphy, Kenji Fujiwara, Jennifer Kleponis, Bulent Salman, Christopher L. Wolfgang, Robert A. Anders, Shu Zheng, Elizabeth M. Jaffee, Lei Zheng

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)5395-5404
Number of pages10
JournalCancer Research
Issue number18
StatePublished - Sep 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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