  The pancreatic innervation undergoes dynamic remodeling during the
development of pancreatic ductal adenocarcinoma (PDAC). Denervation experiments
have shown that different types of axons can exert either pro- or anti-tumor
effects, but conflicting results exist in the literature, leaving the overall
influence of the nervous system on PDAC incompletely understood. To address
this gap, we propose a continuous mathematical model of nerve-tumor
interactions that allows in silico simulation of denervation at different
phases of tumor development. This model takes into account the pro- or
anti-tumor properties of different types of axons (sympathetic or sensory) and
their distinct remodeling dynamics during PDAC development. We observe a "shift
effect" where an initial pro-tumor effect of sympathetic axon denervation is
later outweighed by the anti-tumor effect of sensory axon denervation, leading
to a transition from an overall protective to a deleterious role of the nervous
system on PDAC tumorigenesis. Our model also highlights the importance of the
impact of sympathetic axon remodeling dynamics on tumor progression. These
findings may guide strategies targeting the nervous system to improve PDAC
treatment.
