Abstract
Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro-angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ~12% of PDACs have an angiogenesis gene signature with increased expression of multiple pro-angiogenic genes. By analyzing the recently expanded TCGA dataset, we now report that this signature is present in ~35% of PDACs but that it is mostly distinct from an angiogenesis signature present in pancreatic neuroendocrine tumors (PNETs). These PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, and many members of JAK signaling pathways. Moreover, expression of SMAD4 and HDAC9 correlates with endothelial cell abundance in PDAC tissues. Concomitantly targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib suppresses JAK1 phosphorylation and blocks proliferative cross-talk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs), and these anti-proliferative effects were mimicked by JAK1 silencing in ECs. By contrast, either inhibitor alone does not suppress their enhanced proliferation in 3D co-cultures. These findings suggest that targeting both TGF-β and JAK1 signaling could be explored therapeutically in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature.
Keywords:
TCGA; TGF-β; angiogenesis; inflammation; pancreatic cancer.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Carcinoma, Pancreatic Ductal / blood supply
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Carcinoma, Pancreatic Ductal / genetics*
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Carcinoma, Pancreatic Ductal / metabolism
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Cell Line, Tumor
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Cells, Cultured
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Cluster Analysis
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Coculture Techniques
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Endothelial Cells / metabolism
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Gene Expression Profiling / methods*
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Gene Expression Regulation, Neoplastic*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Humans
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Immunoblotting
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Inflammation Mediators / metabolism
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Janus Kinase 1 / genetics
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Janus Kinase 1 / metabolism
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Neovascularization, Pathologic / genetics*
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Neovascularization, Pathologic / metabolism
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Pancreatic Neoplasms / blood supply
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Smad4 Protein / genetics
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Smad4 Protein / metabolism
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Survival Analysis
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Transforming Growth Factor beta / genetics*
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Transforming Growth Factor beta / metabolism
Substances
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Inflammation Mediators
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Receptors, Transforming Growth Factor beta
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Repressor Proteins
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Smad4 Protein
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Transforming Growth Factor beta
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JAK1 protein, human
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Janus Kinase 1
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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HDAC9 protein, human
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Histone Deacetylases