Dissecting Hedgehog signaling in the mesenchymal and epithelial compartment in K-RasG12D induced pancreatic neoplasia

Background/State of the art. The oncogenic K-Ras mutation represents one of the decisive driver mutations in human pancreatic cancer. Mouse models based on the expression of oncogenic K-Ras recapitulate major features of human pancreatic cancer such as progressive PanIN lesions and expansion of a stromal niche. However, lessons learned from both p48-PTF1a and PDX1 constitutive und inducible driven K-Ras expression clearly indicated that most pancreatic cells seem to be refractory to K-Ras driven transformation despite a small, putative cancer stem cell population. The canonical Hedgehog (Hh) pathway comprises paraand autocrine signals (e.g. sonic hedgehog), cell autonomous negative (e.g. patched) and positive (e.g. smo) regulatory elements merging at Gli transcriptions factors that directly and indirectly activate negative and positive feedback loops (Borggrefe et al., 2016). This network is further complicated due to direct, Ras dependent activation of Gli downstream effectors in the non-canonical Hh-pathway. The Hh-signaling network regulates stemness, epithelial–mesenchymal interactions and pancreatic development and contributes to the initiation and propagation of pancreatic cancer as shown in numerous studies. However, recent findings challenged the underlying mechanisms especially with respect to differential effects of the Hh pathway on the epithelial and mesenchymal compartment and comprehensive morphological studies indicated that only a subpopulation of pancreatic duct cells might be permissive for Hh signaling (Tia et al., 2009; Nolan-Stevaux et al., 2010). Recent evidence further indicates, that the mesenchymal niche might rather suppress pancreatic cancer progression by hitherto unknown mechanisms after epithelial deletion of the Hhpathway secretory component Shh (Rhim et al., 2014). This highly interesting model clearly contradicts a longstanding paradigm that tumor stroma only supports and promotes growth of pancreatic cancer and offers one explanation of clinical failure of stroma-targeting therapies. However, these biological effects are not mutually exclusive and the nature of cellular crosstalk between different components of the microenvironment and the different roles of the members of the Hh signaling network remain to be elucidated.