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

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

Research output: Contribution to journalArticle

26 Scopus citations

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 proangiogenic 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.

Original languageEnglish (US)
Pages (from-to)323-341
Number of pages19
JournalOncotarget
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Angiogenesis
  • Inflammation
  • Pancreatic cancer
  • TCGA
  • TGF-β

ASJC Scopus subject areas

  • Oncology

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