Ciliogenesis and Hedgehog signalling are supressed downstream of KRas during acinar-ductal metaplasia

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths worldwide, but has a dismal 5-year survival rate of only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC it is vital we understand the initiating events that lead to tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanIN) driven by constitutive activation of KRas. In patients PanIN are associated with regions of acinar-ductal metaplasia (ADM), where in response to inflammation acini dedifferentiate to a pancreatic progenitor-like fate. In healthy tissue this process is reversible leading to regeneration of the pancreas however in the presence of oncogenic KRas regeneration is blocked and ADM can give rise to PanIN lesions. Here we have used a 3D acinar culture that recapitulates ADM in vitro to explore how KRas prevents regeneration. Regeneration is regulated by Hedgehog (Hh) signalling, which is transduced via the primary cilium. In WT acini, cilia assemble upon ADM and Hh target gene expression is upregulated however ciliogenesis and Hh signaling is suppressed during ADM in cells expressing oncogenic KRas. We show that ciliogenesis fails due to ectopic activation of the cilium disassembly pathway, which is mediated by AurkA, a direct transcriptional target of KRas. Inhibition of AurkA is able to rescue primary cilia and restore Hh signalling. We suggest this could be used as a mechanism to prevent the formation of early lesions and thereby prevent progression to PDAC.