Molecular determinants of acinar-ductal metaplasia and PanIN lesions
Transdifferentiated acinar cells stained for CK19 (green) and DAPI (blue)
A unique feature of the acinar cell in the adult pancreas is an enormous plasticity. Acinar cells can undergo transdifferentiation to duct-like cells, which represent a progenitor-like cell type. This process termed acinar-ductal metaplasia (ADM) is important to allow pancreatic regeneration but is also a very early and bottleneck event in pancreatic ductal adenocarcinoma (PDAC) initiation. These ductal progenitor-like cells can develop into premalignant cells in response to oncogenic signaling and form pancreatic intraepithelial neoplasia (PanIN), which can progress to PDAC. Although genetically engineered mice harboring KrasG12D in the pancreas recapitulate ADM and PanIN development, little progress has been made in understanding the underlying molecular events and signaling pathways involved.
We aim to systematically investigate different routes of ADM formation using genetically defined murine models. Specifically, we have generated mice with oncogenic gain of function mutations of Pik3ca, Map2k1, and Braf. Unexpectedly, all of these models developed ADM, PanIN and PDAC with different kinetics but morphologically similar to KrasG12D. We will perform holistic studies to determine genetic, epigenetic, molecular, metabolic and signaling requirements to induce this highly plastic cellular state of ADM. We have established a unique combined in vivo and in vitro platform with the aim to identify an “ADM essentialom”. An unbiased PiggyBac transposon-based mutagenesis screening effort will complement these analyses.
The overall aim is to decipher the roadmap to ADM and the heterogeneity of early lesions, which will help to understand PDAC subtypes. In addition, following the concept, that tumor initiation mirrors aspects of tumor maintenance, we propose that our analysis will define novel mechanisms of tumor progression with the potential of therapeutic intervention.
Schonhuber, N., Seidler, B., Schuck, K., Veltkamp, C., Schachtler, C., Zukowska, M., Eser, S., Feyerabend, T. B., Paul, M. C., Eser, P., Klein, S., Lowy, A. M., Banerjee, R., Yang, F., Lee, C. L., Moding, E. J., Kirsch, D. G., Scheideler, A., Alessi, D. R., Varela, I., Bradley, A., Kind, A., Schnieke, A. E., Rodewald, H. R., Rad, R., Schmid, R. M., Schneider, G., and Saur, D. (2014). Nat Med 20, 1340-1347
von Burstin, J., Diersch, S., Schneider, G., Reichert, M., Rustgi, A. K., and Schmid, R. M. (2015). Mol Cancer Res 13, 863-869
Nakhai, H., Siveke, J. T., Mendoza-Torres, L., and Schmid, R. M. (2008). Development 135, 3191-3196
Schmid, R. M., Kloppel, G., Adler, G., and Wagner, M. (1999). Ann Ny Acad Sci 880, 219-230