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Kong, B.* ; Bruns, P. ; Behler, N.A.* ; Chang, L.* ; Schlitter, A.M.* ; Cao, J.* ; Gewies, A. ; Ruland, J.* ; Fritzsche, S.* ; Valkovskaya, N.* ; Jian, Z.* ; Regel, I.* ; Raulefs, S.* ; Irmler, M. ; Beckers, J. ; Friess, H.* ; Erkan, M.* ; Müller, N.S. ; Roth, S.* ; Hackert, T.* ; Esposito, I.* ; Theis, F.J. ; Kleeff, J.* ; Michalski, C.W.*

Dynamic landscape of pancreatic carcinogenesis reveals early molecular networks of malignancy.

Gut 67, 146-156 (2016)

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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

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OBJECTIVE: The initial steps of pancreatic regeneration versus carcinogenesis are insufficiently understood. Although a combination of oncogenic Kras and inflammation has been shown to induce malignancy, molecular networks of early carcinogenesis remain poorly defined. DESIGN: We compared early events during inflammation, regeneration and carcinogenesis on histological and transcriptional levels with a high temporal resolution using a well-established mouse model of pancreatitis and of inflammation-accelerated Kras(G12D)-driven pancreatic ductal adenocarcinoma. Quantitative expression data were analysed and extensively modelled in silico. RESULTS: We defined three distinctive phases-termed inflammation, regeneration and refinement-following induction of moderate acute pancreatitis in wild-type mice. These corresponded to different waves of proliferation of mesenchymal, progenitor-like and acinar cells. Pancreas regeneration required a coordinated transition of proliferation between progenitor-like and acinar cells. In mice harbouring an oncogenic Kras mutation and challenged with pancreatitis, there was an extended inflammatory phase and a parallel, continuous proliferation of mesenchymal, progenitor-like and acinar cells. Analysis of high-resolution transcriptional data from wild-type animals revealed that organ regeneration relied on a complex interaction of a gene network that normally governs acinar cell homeostasis, exocrine specification and intercellular signalling. In mice with oncogenic Kras, a specific carcinogenic signature was found, which was preserved in full-blown mouse pancreas cancer. CONCLUSIONS: These data define a transcriptional signature of early pancreatic carcinogenesis and a molecular network driving formation of preneoplastic lesions, which allows for more targeted biomarker development in order to detect cancer earlier in patients with pancreatitis.

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