CCN1 is a matricellular protein and a member of the CCN family of growth 
factors. CCN1 is associated with the development of various cancers including 
pancreatic ductal adenocarcinoma (PDAC). Our recent studies found that CCN1 
plays a critical role in pancreatic carcinogenesis through the induction of EMT 
and stemness. CCN1 mRNA and protein were detected in the early precursor 
lesions, and their expression intensified with disease progression. However, 
biochemical activity and the molecular targets of CCN1 in pancreatic cancer 
cells are unknown. Here we show that CCN1 regulates the Sonic Hedgehog (SHh) 
signaling pathway, which is associated with the PDAC progression and poor 
prognosis. SHh regulation by CCN1 in pancreatic cancer cells is mediated through 
the active Notch-1. Notably, active Notch-1is recruited by CCN1 in these cells 
via the inhibition of proteasomal degradation results in stabilization of the 
receptor. We find that CCN1-induced activation of SHh signaling might be 
necessary for CCN1-dependent in vitro pancreatic cancer cell migration and 
tumorigenicity of the side population of pancreatic cancer cells (cancer stem 
cells) in a xenograft in nude mice. Moreover, the functional role of CCN1 could 
be mediated through the interaction with the αvβ3 integrin receptor. These 
extensive studies propose that targeting CCN1 can provide a new treatment option 
for patients with pancreatic cancer since blocking CCN1 simultaneously blocks 
two critical pathways (i.e. SHh and Notch1) associated with the development of 
the disease as well as drug resistance.