In vivo and in silico models of early pancreatic carcinogenesis.

Oncogenic Kras mutations are a critical genetic event in early pancreatic carcinogenesis. However, in the adult organ, the expression of mutated Kras alone is not sufficient to induce tissue transformation. Instead, inflammation is required as an aditional trigger. Here, we perform experiments with two well-established models of acute pancreatitis and early pancreatic carcinogenesis, initialized with caerulein injections in wild-type and KrasG12D-mutated mice. Gene expression profiling and histological analysis with a high temporal resolution are applied in order to allow for a comparative analysis of both mouse strains. Based on our findings, we define pancreatic regeneration as process characterized by three distinct stages each showing a specific histological and molecular profile: inflammation, regeneration and refinement. Comparative analysis shows that regeneration in KrasG12D mice is impaired and characterized by a sustained inflammatory status. In addition, we observed that sustained inflammation in KrasG12D mice is accompanied by altered proliferation cascades with respect to acinar, progenitor-like and mesenchymal cells. In particular, a massive mesenchymal expansion is observed. We conclude that these characteristics, sustained inflammation and altered prolifertion cascades, are hallmarks of early pancreatic carcinogenesis mediating precursor lesion formation. We extracted a signature characterizing the inflammatory status and analyzed a datasetof 45 human pancreatic ductal adenocarcinoma (PDAC) with respect to homologous genes ofthis signature. We found that patients could be classified into two distinct clusters, with one exhibiting an increased average survival time (high signature expression) compared to the otherone (low signature expression). According to this finding, we conclude that the inflammatory status could be possibly regarded as an indicator of early pancreatic carcinogenesis. Based on our results, we set up a "dual model" of pancreatic regeneration and early pancreatic carcinogenesis, comprising four states (healthy, inflammation, regeneration and refinement). As divergence of wild-type and KrasG12D profiles starts during the inflammation-regeneration transition in wild-type mice, we assembled correlation-based networks for the corresponding time frame from 3h to 84h in both mouse strains. We found that among the identified interactions of acinar homeostasis-related genes and intercellular signaling-related genes there is a significant enrichment for interaction pairs involving members of the Fgf/Fgfr family, specifically in wild-type mice. Particularly, we found Fgfr3 to be highly connected in the wild-type network, suggesting a potential role in the mediationof the inflammation-regeneration-transition. This finding is in line with recent studies which showed that Fgfr3, which is generally regarded as oncogene, can limit cell growth and promote differentiation if expressed in epithelial cells