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Deprecated: Implicit conversion from float 267.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Cancer+Res 2016 ; 76 (18): 5395-404 Nephropedia Template TP
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Cancer associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation #MMPMID27496707
Xiao Q; Zhou D; Rucki AA; Williams J; Zhou J; Mo G; Murphy A; Fujiwara K; Kleponis J; Salman B; Wolfgang CL; Anders RA; Zheng S; Jaffee EM; Zheng L
Cancer Res 2016[Sep]; 76 (18): 5395-404 PMID27496707show ga
Stromal fibrosis is a prominent histological 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 (MSC) 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 IGF-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 tumor microenvironment which promote malignant growth and progression.