Hedgehog signaling stimulates Tenascin C to promote invasion of pancreatic ductal adenocarcinoma cells through Annexin A2.
Pancreatic adenocarcinoma (PDA) is characterized by a dense desmoplastic reaction that comprises 60-90% of the tumor, while only 10-40% of the tumor is composed of malignant epithelial cells. This desmoplastic reaction is composed of stromal fibroblast cells, extracellular matrix proteins, and immune cells. Accumulating evidence has suggested that the stromal and epithelial cell compartments interact during the pathogenesis of this disease. Therefore, it is important to identify the signaling pathways responsible for this interaction to better understand the mechanisms by which PDA invades and metastasizes. Here, we show that secreted stromal factors induce invasion of PDA cells. Specifically, hedgehog signaling from the tumor cells induces tenascin C (TnC) secretion from the stromal cells that acts back upon the tumor cells in a paracrine fashion to induce the invasion of PDA cells through its' receptor annexin A2 (AnxA2). Therefore, blocking the interaction between TnC and AnxA2 has the potential to prevent liver metastasis in PDA.
a The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.|b Department of Oncology , Johns Hopkins University School of Medicine , Baltimore , MD , USA.|c The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine , Baltimore , MD , USA.|d Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine , Baltimore , MD , USA.
Kelly
K
Foley
a The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.|b Department of Oncology , Johns Hopkins University School of Medicine , Baltimore , MD , USA.|c The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine , Baltimore , MD , USA.
Stephen
http://orcid.org/0000-0001-9381-3921
S
Muth
a The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.|b Department of Oncology , Johns Hopkins University School of Medicine , Baltimore , MD , USA.|c The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine , Baltimore , MD , USA.
Elizabeth
E
Jaffee
a The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore , MD , USA.|b Department of Oncology , Johns Hopkins University School of Medicine , Baltimore , MD , USA.|c The Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine , Baltimore , MD , USA.|e Department of Surgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA.
Lei
L
Zheng
D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019063:Tenascin / Q000235:genetics / Q000378:metabolism
D017306:Annexin A2; D019063:Tenascin
annexin A2; hedgehog; pancreas cancer; stroma; tenascin C