Oncotarget

Research Papers:

Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes

Kelly E. Craven, Jesse Gore _, Julie L. Wilson and Murray Korc

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:323-341. https://doi.org/10.18632/oncotarget.6345

Metrics: PDF 2929 views  |   HTML 9205 views  |   ?  


Abstract

Kelly E. Craven1,*, Jesse Gore2,3,*, Julie L. Wilson2, Murray Korc1,2,3

1Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

2Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

3The Pancreatic Cancer Signature Center at Indiana University Simon Cancer Center, Indianapolis, IN 46202, USA

*These authors contributed equally to this work

Correspondence to:

Jesse Gore, e-mail: [email protected]

Keywords: pancreatic cancer, TCGA, angiogenesis, TGF-β, inflammation

Received: October 13, 2015     Accepted: November 08, 2015     Published: November 18, 2015

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6345