Pancreatic Ductal Adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival of 7%. While human PDACs (hPDACs) are hypovascular, they also overexpress a number of angiogenic growth factors and receptors. Additionally, the use of anti-angiogenic agents in murine models of PDAC leads to reduced tumor volume, tumor spread, and microvessel density, and improved survival. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful in hPDAC. On the other hand, pancreatic neuroendocrine tumors (PNETs) account for only 2% of pancreatic tumors, yet they are very vascular and classically angiogenic, respond to anti-angiogenic therapy, and confer a better prognosis than PDAC even in the metastatic setting.

By analyzing the recently expanded TCGA (The Cancer Genome Atlas) dataset, we report here that an angiogenesis gene signature is present in ∼35% of PDACs and is mostly distinct from an angiogenesis signature present in PNETs. Additionally, principal component analysis (PCA) of the entire or angiogenic PDAC and PNET transcriptomes from TCGA indicates that there are large differences in gene expression between these two tumor types. For example, PDACs exhibit a transcriptome that reflects active TGF-β signaling, and up-regulation of several pro-inflammatory genes, including members of JAK signaling pathways. Functionally, targeting the TGF-β type I receptor (TβRI) kinase with SB505124 and JAK1-2 with ruxolitinib blocks proliferative cross-talk between human pancreatic cancer cells and human endothelial cells. Tumors from the KRC (oncogenic Kras, deleted Rb1) PDAC mouse model show superior enrichment and differential expression of the angiogenic gene signature compared to tumors from the KPC (oncogenic Kras, mutated Trp53) PDAC mouse model. Moreover, treatment of KRC and KPC mice with ruxolitinib suppresses murine PDAC progression in KRC mice but not in KPC mice. These findings suggest that targeting both TGF-β and JAK signaling in the 35% of PDAC patients whose cancers exhibit an angiogenesis gene signature should be explored in the clinic and that this could lead to improved responses to anti-angiogenic therapy in PDAC.

Citation Format: Kelly E. Craven, Jesse Gore, Julie L. Wilson, Murray Korc. An angiogenesis gene signature points to active TGF-beta/JAK signaling pathways in a subset of human pancreatic ductal adenocarcinoma cancer patients that are distinct from pathways in pancreatic neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3400.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.