Cancer-Associated Fibroblasts in Pancreatic Cancer Are Reprogrammed by Tumor-Induced Alterations in Genomic DNA Methylation.

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.

[1]  Umar Mahmood,et al.  Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. , 2015, Cancer cell.

[2]  C. Iacobuzio-Donahue,et al.  Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer , 2015, Science Signaling.

[3]  P. Greenberg,et al.  Stromal reengineering to treat pancreas cancer. , 2014, Carcinogenesis.

[4]  Stephen A. Sastra,et al.  Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. , 2014, Cancer cell.

[5]  A. Sharma,et al.  The Role of Suppressors of Cytokine Signalling in Human Neoplasms , 2014, Molecular biology international.

[6]  A. Rucki,et al.  Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies. , 2014, World journal of gastroenterology.

[7]  S. Anant,et al.  DNA Methyltransferases: A Novel Target for Prevention and Therapy , 2013, Front. Oncol..

[8]  P. Tassone,et al.  miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells , 2013, Cell cycle.

[9]  M. Magliano,et al.  Deciphering the role of stroma in pancreatic cancer , 2013, Current opinion in gastroenterology.

[10]  E. Fishman,et al.  Recent progress in pancreatic cancer , 2013, CA: a cancer journal for clinicians.

[11]  Lei Shi,et al.  Hepatocellular carcinoma‐associated mesenchymal stem cells promote hepatocarcinoma progression: Role of the S100A4‐miR155‐SOCS1‐MMP9 axis , 2013, Hepatology.

[12]  S. Pandol,et al.  A starring role for stellate cells in the pancreatic cancer microenvironment. , 2013, Gastroenterology.

[13]  C. Scarlett Contribution of bone marrow derived cells to the pancreatic tumor microenvironment , 2013, Front. Physiol..

[14]  B. Tycko,et al.  Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma. , 2013, Cancer research.

[15]  E. Lengyel,et al.  MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. , 2012, Cancer discovery.

[16]  Seung‐Mo Hong,et al.  Unlike Pancreatic Cancer Cells Pancreatic Cancer Associated Fibroblasts Display Minimal Gene Induction after 5-Aza-2′-Deoxycytidine , 2012, PloS one.

[17]  Derek S. Chan,et al.  The Pancreas Cancer Microenvironment , 2012, Clinical Cancer Research.

[18]  King-Jen Chang,et al.  Breast Cancer Cells Induce Stromal Fibroblasts to Secrete ADAMTS1 for Cancer Invasion through an Epigenetic Change , 2012, PloS one.

[19]  Keith D Robertson,et al.  DNA methylation: superior or subordinate in the epigenetic hierarchy? , 2011, Genes & cancer.

[20]  A. Maitra,et al.  Tyrosine 23 Phosphorylation-Dependent Cell-Surface Localization of Annexin A2 Is Required for Invasion and Metastases of Pancreatic Cancer , 2011, PloS one.

[21]  C. Farquharson,et al.  The effect of GH and IGF1 on linear growth and skeletal development and their modulation by SOCS proteins. , 2010, The Journal of endocrinology.

[22]  Frédérick A. Mallette,et al.  SOCS1, a novel interaction partner of p53 controlling oncogene-induced senescence , 2010, Aging.

[23]  Pedram Argani,et al.  MethySYBR, a novel quantitative PCR assay for the dual analysis of DNA methylation and CpG methylation density. , 2009, The Journal of molecular diagnostics : JMD.

[24]  Miguel Pignatelli,et al.  CROC: finding chromosomal clusters in eukaryotic genomes , 2009, Bioinform..

[25]  Seung‐Mo Hong,et al.  Pancreatic cancer associated fibroblasts display normal allelotypes , 2008, Cancer biology & therapy.

[26]  Kylie L. Gorringe,et al.  No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas , 2008, Nature Genetics.

[27]  P. Platzer,et al.  Breast-cancer stromal cells with TP53 mutations and nodal metastases. , 2007, The New England journal of medicine.

[28]  A. Mannermaa,et al.  Frequent gene dosage alterations in stromal cells of epithelial ovarian carcinomas , 2006, International journal of cancer.

[29]  Robert A. Weinberg,et al.  Stromal Fibroblasts in Cancer: A Novel Tumor-Promoting Cell Type , 2006, Cell cycle.

[30]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[31]  L. Coussens,et al.  Tumor stroma and regulation of cancer development. , 2006, Annual review of pathology.

[32]  K. Schuebel,et al.  Differential requirement for DNA methyltransferase 1 in maintaining human cancer cell gene promoter hypermethylation. , 2006, Cancer research.

[33]  Jun Yao,et al.  Distinct epigenetic changes in the stromal cells of breast cancers , 2005, Nature Genetics.

[34]  H. Moses,et al.  Stromal fibroblasts in cancer initiation and progression , 2004, Nature.

[35]  N. Fusenig,et al.  Friends or foes — bipolar effects of the tumour stroma in cancer , 2004, Nature Reviews Cancer.

[36]  W. Leung,et al.  Quantitative detection of methylated SOCS-1, a tumor suppressor gene, by a modified protocol of quantitative real time methylation-specific PCR using SYBR green and its use in early gastric cancer detection , 2004, Biotechnology Letters.

[37]  M. Emi,et al.  Hypermethylation-associated inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human pancreatic cancers. , 2004, Japanese journal of clinical oncology.

[38]  R. Hruban,et al.  Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms , 2003, British Journal of Cancer.

[39]  J. Herman,et al.  Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas. , 2003, Carcinogenesis.

[40]  W. Alexander,et al.  Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction , 1999, Journal of leukocyte biology.

[41]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[42]  R. Hruban,et al.  Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials. , 1998, The cancer journal from Scientific American.