title: Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes.
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.
authors.affiliation: Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Craven
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|The Pancreatic Cancer Signature Center at Indiana University Simon Cancer Center, Indianapolis, IN 46202, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Gore
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Wilson
authors.affiliation: Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.|The Pancreatic Cancer Signature Center at Indiana University Simon Cancer Center, Indianapolis, IN 46202, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016000:Cluster Analysis; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D018125:Receptors, Transforming Growth Factor beta; D012097:Repressor Proteins; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
keywords: TCGA; TGF-β; angiogenesis; inflammation; pancreatic cancer