Generation of fibronectin fragments by pancreatic trypsin: a physiological mechanism hampering PDAC progression.

In this study we demonstrate that spheroids isolated from normal pancreas and co-trasplanted with PDAC orthotopically in mouse pancreas , inhibited tumor growth. Fibronectin proteolytic fragments generated by trypsin and released by pancreatic spheroids, were responsible for of the observed effect. Specifically, in vitro analysis revealed that FAK and FGFR1 signalling were turned off in tumor cells inducing tumor cell detachment, indicating a cooperative activity between the two signalling pathways. This mutual relationship was confirmed by the addition of FGF2 that reversed both FGFR1 and FAK defosphorilation and promoted PDAC cell adhesion and proliferation. Mass spectrometry proteomic analysis and the use of mAb allowed the identification of the FN fragments belonging to the Type III domain responsible of PDAC inhibition. Finally, the effect of FAK and FGFR signalling inhibitors was tested in combination both in vivo and in vitro to emulate the effect of normal pancreatic spheroids on PDAC growth.